Tetrahedron 69 (2013) 4120e4138

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Tetrahedron
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Novel method for construction of tetrahydro-1-benzazepine and

tetrahydro-2-benzazepine based on 7-endo selective FriedeleCrafts
cyclization of vinyloxirane
Megumi Mizukami a, Koji Wada a, Gen Sato a, Yusuke Ishii a, Norio Kawahara a,
Shinji Nagumo b, *
a
Hokkaido Pharmaceutical University, School of Pharmacy, Katsuraoka 7-1, Otaru, Hokkaido 047-0264, Japan
b
Department of Applied Chemistry, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan

a r t i c l e i n f o a b s t r a c t

Article history: The 7-endo FriedeleCrafts cyclization of vinyloxiranes, which have a nitrogen atom at the linker between
Received 20 September 2012 the aromatic ring and the epoxide, was found to proceed regio- and stereoselectively to afford poly-
Received in revised form 1 March 2013 functional tetrahydro-1-benzazepine and tetrahydro-2-benzazepine.
Accepted 5 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 13 March 2013

1. Introduction some Amaryllidaceae alkaloids such as montanine,5 based on FC cy-

Tetrahydrobenzazepines are important heterocycles containing
seven-membered cyclic amine. In particular, tetrahydro-2-benzaz-
epine is present as a key structural unit in a kind of Amaryllidaceae
alkaloids showing biological activities. Stereoselective synthetic
methods of polyfunctionalized tetrahydrobenzazepines therefore
have attracted much attention. Meanwhile, the chemistry of epox-
ides has been widely accepted as a convenient synthetic tool mainly
as a result of their stereospecific ring-opening with various nucleo-
philes and their potential as building blocks for the synthesis of
a wide range of biologically active compounds. The epoxide-opening
by external- and also internal-nucleophiles necessitates excellent
regiochemical control between two reacting cites in order to make
itself more practical. Taylor et al. investigated systematically intra-
molecular FriedeleCrafts (FC) reaction of various arylalkyl epoxides.1
In the course of their study, 1 underwent 7-exo cyclization upon
treatment with SnCl4 to produce 2 in moderate yield (Scheme 1). On
the other hand, epoxide 4 preferred 6-exo cyclization rather than 7-
endo one to afford 5 and 6. We previously developed a novel ap-
proach for selective 7-endo cyclization by linking a vinyl group to
epoxides, wherein vinyloxirane 7 was converted into seven-
membered carbocycle 8 in excellent yield.2,3 If the generic sub-
strate has a nitrogen atom at the linker between the aromatic ring
and epoxide, a 7-endo selective FC cyclization will result in con-
struction of seven-membered cyclic amines. We herein report a new
efficient method of polyfunctional tetrahydro-1-benzazepine and
tetrahydro-2-benzazepine,4 which is a common central moiety of
* Corresponding author. E-mail address: bt13071@ns.kogakuin.ac.jp (S. Nagumo).
clization of vinyloxiranes 25e27.
2. Results and discussion
Vinyloxiranes 25e27 were prepared from the corresponding
benzylsulfonamides 9aed or phenylsulfonamides 17aec
(Scheme 2). Alkylation of 9aed with 1,4-dichlorobut-2-ene affor-
ded allyl chloride 10aed, which was converted into allyl alcohol
12aed through substitution with CH3COONa and subsequent
methanolysis.6 Compound 9c was also subjected to allylation with
allyl bromide. Hydroboration of the obtained allylamine 13 fol-
lowed by treatment with H2O2 gave alcohol 14, which was trans-
formed to 15 by the sequence of DesseMartin oxidation7 and
Wittig reaction. Reduction of 15 with DIBAH produced allyl alcohol
16. Allyl alcohols 21aec were also prepared from 17aec by the
same synthetic route as that of 16. Epoxidation of 12aed, 16, 21aec
produced the corresponding 22e24, which were finally converted
into 25aed, 26, 27aec by DesseMartin oxidation and subsequent
Wittig reaction.
As the start of this research, we tried FC reaction of 25a by the
same method as the seven-membered carbocyclization2,3 of 7
previously reported by us. Treatment of 25a with BF3$Et2O in
CH2Cl2 at
30  C afforded no hydro-2-benzazepine but gave un-
expected aminal 28a in 25% yield (Scheme 3). Such an aminal for-
mation is rationalized as follows. Vinyloxirane 25a undergoes ipso-
cyclization at the epoxide carbon adjacent to a vinyl group to
produce a spiro-cyclic benzenium ion A. The regiochemical control
for the ring opening of oxirane is ascribed to the resonance effect by
the vinyl group.8 Fragmentation9 of A triggered by electron-

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 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138 4121

OH
O OH
SnCl4
65%
+

1 2 : 3 = ca. 3: 1 2 3

O CH2OH OMe CH2OH

SnCl4
95% +
MeO MeO

4 5 : 6 = ca. 1.6 : 1 5 6

MeOOC MeOOC
BF3 . Et2O
O CH2Cl2 OH
-30 oC

MeO 97% MeO

7 8
Scheme 1.

releasing of a nitrogen atom generates iminium ion B. An internal 25b possessing C30 -methoxy group on benzene ring undergoes
hydroxy group attacks the generated ion to afford 28a. Fortunately, both para- and ortho-cyclizations, generating hydro-2-benzazepine
activation of the benzene ring by introducing a methoxy group compounds 29b (71%) and 30b (12%). However, the extent of the
made it possible to construct a seven-membered ring. Vinyloxirane seven-membered cyclization was greatly diminished by further

Cl AcO HO
R2
a R2 b R2 c R2
NHTs
R1

9a (R1=R2=H) R1 N R1 N R1 N
9b (R1=OMe, R2=H) Ts Ts 63-69% (3 steps) Ts
9c (R1=R2=OMe) 10a-d 11a-d 12a-d
9d (R1=R2= -OCH2O-) HO
COOMe
MeO HO MeO MeO
d MeO e f g
9c
MeO MeO N MeO MeO
N N N
Ts Ts Ts
92% 84% 85% 88% Ts
13 14 15 16
OH
R3 R3 R3 OH R3 COOMe R3
R2 d R2 e R2 f R2 g R2

R1 NHTs 98->99% R1 N R1 N R1 N R1 N
Ts Ts Ts Ts
17a (R1=OMe, R2=R3=H) 84-96% 52-83% 83-85%
17b (R1=R2= OMe, R3=H) 18a-c 19a-c 20a-c 21a-c
17c (R1=R3= OMe, R2=H)
MeOOC
HO HO
R3 R3 O R3 O
R2 h R2 f R2
25a (n = 1, m = 0, R1=R2=R3=H)
25b (n = 1, m = 0, R1=OMe, R2=R3=H)
R1 ( )n N ( )m R1 ( )n N ( )m R1 ( )n N ( )m 25c (n = 1, m = 0, R1=R2=OMe, R3=H)
25d (n = 1, m = 0, R1=R2= -OCH2O-, R3=H)
Ts 59-93% Ts 62-92% Ts 26 (n = 1, m = 1, R1=R2=OMe, R3=H)
12a-d (n = 1, m = 0) 22a-d (n = 1, m = 0) 27a (n = 0, m = 1, R1=OMe, R2=R3=H)
16 (n = 1, m = 1) 23 (n = 1, m = 1) 27b (n = 0, m = 1, R1=R2=OMe, R3=H)
21a-c (n = 0, m = 1) 24a-c (n = 0, m = 1) 27c (n = 0, m = 1, R1=R3=OMe, R2=H)
Scheme 2. (a) NaH, ClCH2CH]CHCH2Cl, DMF; (b) CH3COONa, DMF, 120  C; (c) K2CO3, MeOH; (d) NaH, CH2]CHCH2Br, DMF; (e) (1) 9-BBN, THF (2) NaOH aq, H2O2 aq; (f) (1)
DesseMartin periodinane, CH2Cl2 (2) Ph3P]CHCOOMe; (g) DIBAH, CH2Cl2; (h) MCPBA, CH2Cl2.
4122 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138

COOMe
MeOOC MeOOC O
BF3 . Et2O N Ts
OH MeOOC
O CH Cl OH
2 2

N
N -30 oC N Ts 25%
Ts Ts
25a A B 28a

COOMe
MeOOC MeOOC
BF3 . Et2O O
N Ts MeO
O MeOOC OH OH
CH2Cl2
+ +
MeO 3' N -30 oC MeO N N
Ts MeO Ts Ts

25b 28b (17%) 29b (71%) 30b (12%)

COOMe
O MeOOC
N Ts
BF3 . Et2O MeOOC
O OH
MeO 4' CH2Cl2
MeO
+
MeO 3' N o
-30 C MeO MeO N
Ts OMe Ts

25c 28c (79%) 29c (15%)

COOMe
O
N Ts
BF3 . Et2O MeOOC
O
O CH2Cl2

O
N -30 oC O
Ts O

25d 28d (79%)

Scheme 3. BF3$Et2O-promoted reaction of 25aed.

introduction of a methoxy group to the C40 position. Treatment of
25c with BF3$Et2O in CH2Cl2 at
30  C gave aminal 28c (79%) as
a major product and hydrobenzazepine 29c (15%). Higher yield of
aminal 28c than that of 28b can be rationalized by considering that
a methoxy group at the C40 position accelerates ipso-cyclization.
Vinyloxirane 25d with a methylenedioxy group was only converted
into aminal 28d under the present conditions.
Since formation of hydrobenzazepines shown in Scheme 3 was
less satisfactory except for the reaction of 25b, we next investigated
a Lewis acid allowing for more facile 7-endo cyclization. As a result,
it turned out that trialkylsilyltriflates were liable to produce
hydrobenzazepines. Treatment of 25c with triethylsilyltriflate
(TESOTf) at
30  C afforded hydrobenzazepine 29c in 49% yield
along with aminal 28c (Scheme 4). Replacement of the Lewis acid
by trimethylsilyltriflate (TMSOTf) facilitated the seven-membered
cyclization to generate 29c in 67% yield. Furthermore, when
treated with TMSOTf at 0  C, 25c was predominantly converted
into 29c in 91% yield after 3 h. HPLC monitoring of the reaction
mixture showed that 28c was formed as a major product at an early
stage of this reaction.10 Having conceived of the subsequent con-
version of aminal 28c into hydrobenzazepine 29c in the present
reaction, we next confirmed the behavior of isolated aminal 28c by
treatment with Lewis acids. Aminal 28c was completely trans-
formed into 29c within 30 min at 0  C upon treatment with
TMSOTf. On the other hand, BF3$Et2O had little effect on the con-
version. It can be concluded from these results that TMSOTf-
promoted FC cyclization of 25c includes two routes: direct attack
of the benzene ring at the ortho position to the alkyl side chain
(route a) and a tandem route that consists of 6-endo ipso-cycliza-
tion (route b), fragmentation (route c) and FC cyclization of the
generated iminium ion (route d).
The present conditions were applied to other vinyloxiranes 25b
and 25d (Scheme 5). When treated with TMSOTf at
30  C, the
reaction of 25b exhibited a result similar to that using BF3$Et2O.
Thus, two kinds of hydrobenzazepines 29be30b and aminal 28b
were obtained in 66%, 13%, and 21% yields, respectively. On the
other hand, when the TMSOTf-promoted reaction was carried out
at 0  C, four regional isomers of hydrobenzazepines 29be32b were
generated in 61%, 13%, 15%, and 2% yields, respectively. Among
them, formation of 31b and 32b was ascribed to the tandem route
via iminium ions, whereas one of 29b and 30b was ascribed to the
direct seven-membered cyclization. Furthermore, TMSOTf exerted
an effect on the 7-endo cyclization of also 25d producing 29d in 51%
yield.
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138 4123

COOMe MeOOC

a O OH
MeO R3SiOTf MeO
b CH2Cl2
MeO N MeO N
Ts
Ts route a
25c 29c
R3SiOTf
route b route d
CH2Cl2
O
COOMe OMe COOMe N Ts
MeOOC
MeO
MeO e
OH OH
MeO route c d MeO
N N route e
OMe
Ts Ts
28c

R3SiOTf Temp. 28c 29c

TESOTf -30 oC 28% 49%

TMSOTf -30 oC 5% 67%
o
TMSOTf 0 C 91%

O MeOOC
N Ts TMSOTf
MeOOC
CH2Cl2
OH
0 oC MeO

MeO 94% MeO N

OMe Ts
28c 29c
Scheme 4. TMSOTf-promoted 7-endo FriedeleCrafts cyclization of 25c.

We also tried the 8-endo FC cyclization of 26 with BF3$Et2O or
TMSOTf (Scheme 6). Hydro-2-benzazocine 34 was obtained in fairly
good yields in both cases, although a pyrrolidine formation con-
comitant with elimination of benzyl group and an aminal formation
proceed as competitive reactions.
Having succeeded in constructing hydro-2-benzazepines, we
turned our attention to the 7-endo FC cyclization of vinyloxirane
27aec, which could generate hydro-1-benzazepines (Scheme 7).
Compound 27a possessing a methoxy group at the C30 position failed
to undergo 7-endo FC cyclization upon treatment with BF3$Et2O but
underwent exclusive ring closure of nitrogen to produce pyrrolidines
36e38. However, construction of hydro-1-benzazepine has been
achieved by introducing further a methoxy group on a benzene ring.
Vinyloxirane 27b with methoxy groups at the C30 and C40 positions
was stereospecifically transformed into the desired product 39b in
excellent yield upon treatment with both BF3$Et2O and TMSOTf.
Similarly, a direct 7-endo cyclization of 27c with BF3$Et2O or TMSOTf
proceeded smoothly to afford 39c in good yield.
In order to demonstrate the synthetic utility of our newly de-
veloped method, we next performed the construction of the com-
mon tetracyclic skeleton in montanine type alkaloids (Scheme 8).11,12
The coupling reaction of optically active epoxide 4013 and sulfon-
amide 9c with Pd(PPh3)4 and Et3N in CH3CN proceeded with double
inversion to afford ester 41 in 87% yield.14,15 Compound 41 was
converted to benzyl ether 42 in four steps (79%): (i) catalytic
hydrogenation with Pd(OH)2/C; (ii) silylation with TBDPSCl and
imidazole; (iii) reduction of ester group with LiAlH4 in THF; (iv)
benzylation with BnBr, KI, and NaH. Compound 42 was transformed
to allyl alcohol 43 by a three-step reaction sequence: (i) removal of
TBDPS group with TBAF in THF; (ii) DesseMartin oxidation followed
by Wittig reaction with Ph3P]CHCO2Me; (iii) reduction of DIBAH in
toluene. The allyl alcohol 43 was converted to vinyloxirane 44 in two
steps: (i) KatsukieSharpless epoxidation with L-DIPT;16 (ii)
DesseMartin oxidation followed by Wittig reaction with Ph3P]
CHCO2Me. Upon treatment with TMSOTf in CH2Cl2 at 0  C, the key-
step cyclization of 44 proceeded stereoselectively to give hydro-
benzazepine 4517 with a C4 side chain unit in 87% yield. In order to
perform the transannulation across a seven-membered cyclic amine
as a next issue, 45 was subjected to ozonolysis followed by treatment
with NaBH4 producing a diol in moderate yield, whose primary- and
secondary-hydroxy groups were protected by TBDPS and benzyl
groups, respectively. The obtained 46 was converted to the bridged
cyclic intermediate 47 in three steps: (i) removal of TBDPS group
with TBAF in THF; (ii) removal of tosyl group with sodium naph-
thalenide in DME; (iii) transannulation of the resulting aminoalcohol
upon treatment with Ph3P, imidazole, and I2. Hydrogenolysis of
benzyl ether 47 followed by selective protection of primary alcohol
by TBDPS group and acetylation of secondary alcohol. After desily-
lation of the obtained 48 with TBAF in THF, the resulting alcohol was
oxidized by DesseMartin periodinane to produce aldehyde 49.
4124 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138

COOMe
MeOOC
O
N Ts
O TMSOTf MeOOC
OH
CH2Cl2
MeO N
+
MeO N
Ts MeO Ts
25b 28b 29b
MeOOC MeOOC MeOOC

MeO OH OH OH
MeO
+ +
N N N
Ts Ts OMe Ts

30b 31b 32b

28b 29b 30b 31b 32b

-30 oC 21% 66% 13%

o
0 C 61% 13% 15% 2%

COOMe MeOOC
O
TMSOTf N Ts
MeOOC
O OH
O CH2Cl2
O
0 oC +
O O N
N
O Ts
Ts
O

25d 28d (18%) 29d (51%)

Scheme 5. TMSOTf-promoted 7-endo FriedeleCrafts cyclization of 25b and 25d.

MeOOC Ts
O N
MeOOC
O MeOOC
OH HO
MeO CH2Cl2
MeO
o
+ + MeOOC N
MeO -30 C
N MeO MeO Ts
N
Ts OMe Ts
26 33 34 35

BF3 . Et2O 12% 39% 22%

TMSOTf 16% 46% 28%

Scheme 6.

The treatment of 49 with methyl Grignard reagent resulted in for- 3. Conclusion

mation of alcohol 50 (40%) and diol 51 (16%). Among them, 50 was
subjected to hydrolysis under mild alkaline conditions giving diol 51.
Subsequent oxidation of the diol 51 with TPAP afforded the diketone
52, of which aldol reaction was successfully performed using KOH in
EtOH at room temperature giving aldol 53 (64%) and enone 54 (12%).
Further treatment of the generated 53 with KOH in EtOH at 60  C
furnished 5,11-methanomorphanthridine analog 54, which is
a common central moiety of some Amaryllidaceae alkaloids such as
montanine.
In conclusion, a new method for construction of hydro-1-
benzazepines and hydro-2-benzazepines has been developed based
on 7-endo selective FC cyclization of vinyloxiranes, which have a ni-
trogen atom at the linker between the aromatic ring and the epoxide.
Each cyclization exhibits excellent stereoselectivity and regiose-
lectivity, which is ascribed to the resonance effect of the vinyl group.
Formation of hydro-2-benzazepines includes two mechanistic
routes: direct 7-endo cyclization and a sequential route, which
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138 4125

COOMe
Ts

O TMSOTf
N N N
CH2Cl2
OH OTs OH
MeO + MeO + MeO
MeO N -30 oC
MeOOC MeOOC MeOOC
Ts

27a 36 (33%) 37 (19%) 38 (5%)

COOMe MeOOC

O Lewis acid OH
MeO CH2Cl2 MeO

-30 oC Lewis acid Yield

MeO N MeO N
Ts Ts BF3. Et2O 95%
TMSOTf 99%
27b 39b

COOMe MeOOC

MeO MeO OH
O Lewis acid
CH2Cl2

MeO N -30 oC MeO N Lewis acid Yield

Ts Ts .
BF3 Et2O 63%

27c 39c TMSOTf 75%

Scheme 7.

consists of ipso cyclization, Grob type fragmentation and FC cycliza-
tion of the generated iminium ion. Determining factors of them are
Lewis acid and substituent pattern for the benzene ring of substrates.
On the other hand, formation of hydro-1-benzazepines should pro-
ceed via only the direct route. Since pyrrolidine formation occurs as
a competitive reaction, sufficient activation of the benzene ring is
essential for smooth construction of a hydro-1-benzazepine skeleton.
The synthetic utility of these reactions was further demonstrated by
synthesizing 5,11-methanomorphanthridine analog 54, which had
a complete framework common to some Amaryllidaceae alkaloids
such as montanine, based on 7-endoselective FC cyclization of
vinyloxiranes 44.
4. Experimental
4.1. General procedure
The melting points were determined on a Yanaco micro melting
point apparatus and were uncorrected. Optical rotations were
measured with a JASCO DIP-370 or a JASCO P-2300. IR spectra were
recorded on a JASCO IRA-102, a JASCO FT-IR-7000 spectrometer or
a Perkin Elmer Spectrum 100 FT-IR spectrometer. NMR spectra
were recorded on a JEOL GX-270, a JEOL AL-400, or a JEOL ECA-600
spectrometer using tetramethylsilane as an internal standard.
Chemical shifts are given in parts per million (ppm). The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet;
br, broad. MS spectra were measured on a Hitachi M-2000 in-
strument or JEOL MStation 700. Elemental analyses were per-
formed using a Perkin Elmer 2400II. Column chromatography was
carried out on Merck’s Silica gel 60 (70e230 mesh ASTM) or Kanto
Silica Gel 60 (63e210 mm).
4.2. Synthesis of vinyloxiranes
4.2.1. N-Benzyl-N-[(2E)-4-hydroxy-2-butenyl]-4-methylbenzenes-
ulfonamide (12a). To a solution of 9a (2.25 g, 8.59 mmol) in DMF
(170 mL) were added NaH (60% oil dispersion 519 mg, 13.0 mmol,
1.5 equiv) and trans-1,4-dichrolobut-2-ene (2.75 mL, 26.2 mmol,
3 equiv) at 0  C. The mixture was stirred for 5 h at room temper-
ature, then quenched with H2O, and extracted with Et2O. The ex-
tract was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with n-hexane/AcOEt (1:1) to give 10a (2.22 g,
6.33 mmol) as a colorless oil: To a solution of 10a in DMF (120 mL)
was added AcONa (1.04 g, 12.7 mmol, 2 equiv) at 0  C. The solution
was stirred for 3 h at 120  C and was added to saturated K2CO3/
MeOH (100 mL) at 0  C. After an additional 3 h stirring, the reaction
mixture was quenched with H2O, extracted with Et2O, and washed
with brine. The extract was dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel eluted with n-hexane/AcOEt (2:1) to
give 12a (1.77 g, 5.35 mmol, 63%) as a colorless oil; IR (ATR) 3493,
2918, 1597 cm
1; MS (SIMSþ) m/z 332 (MþHþ), 314, 277; HRMS m/
z calcd for C18H22NO3S: 332.1320, found 332.1347; 1H NMR
(270 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.31 (d, J¼8.2 Hz, 2H),
7.36e7.20 (m, 5H), 5.54 (dt, J¼15.1, 5.2 Hz, 2H), 5.35 (dt, J¼15.1,
6.5 Hz, 2H), 4.31 (s, 2H), 3.92 (br s, 2H), 3.72 (d, J¼6.5 Hz, 2H), 2.43
(s, 3H); 13C NMR (68 MHz, CDCl3) d 143.2 (C), 137.0 (C), 136.1 (C),
133.8 (CH), 129.7 (CH2), 128.4 (CH4), 127.6 (CH), 127.1 (CH2),
125.4 (CH), 62.4 (CH2), 50.7 (CH2), 48.6 (CH2), 21.4 (CH3).
4.2.2. N-[(2E)-4-Hydroxy-2-butenyl]-N-(3-methoxybenzyl)-4-
methylbenzenesulfonamide (12b). According to the conversion of 9a
4126 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138

OH TBDPSO OBn
a MeO CO2Et b-e MeO f-h
O
CO2Et
MeO NTs MeO NTs
40
41 42
MeOOC MeOOC
HO
OBn O OBn OH OBn
MeO i-j MeO k MeO

MeO NTs MeO NTs MeO NTs

43 44 45

OTBDPS
l-n OBn OBn o-q OBn OBn r-t OAc OTBDPS
MeO MeO MeO

MeO NTs MeO N MeO N

46 47 48
OAc OAc OH OH OH
u-v MeO CHO w MeO MeO
+
MeO N MeO N MeO N
49 50 51
x

O O
O O HO
y MeO z MeO MeO
+
MeO N MeO N H MeO N H
52 53 54
aa

Scheme 8. (a) 9c, Pd(PPh3)4, Et3N, CH3CN, 87%; (b) Pd(OH)2/C, H2, EtOH, 98%; (c) TBDPSCl, imidazole, THF, 85%; (d) LiAlH4, THF; (e) NaH, BnBr, KI, THF, reflux, 97% (two steps); (f)
TBAF, THF, 92%; (g) DesseMartin periodinane, CH2Cl2, then Ph3P]CHCO2Me, 82%; (h) DIBAH, toluene,
20  C, 94%; (i) L-DIPT, Ti(OiPr)4, TBHP, CH2Cl2,
30  C, 78%; (j) DesseMartin
periodinane, CH2Cl2, then Ph3P]CHCO2Me, 90%; (k) TMSOTf, CH2Cl2, 0  C, 87%; (l) (1) O3, CH2Cl2, (2) NaBH4, MeOH, 54% (two steps); (m) TBDPSCl, Et3N, DMAP, CH2Cl2, 89%; (n)
BnBr, NaH, THF, 89%; (o) TBAF, THF, 97%; (p) naphthalene, Na, 1,2-dimethoxyethane; (q) Ph3P, imidazole, I2, CH3CN, ether, 82% (two steps); (r) Pd(OH)2/C, conc. HCl, MeOH, 96%; (s)
TBDPSCl, Et3N, DMAP, CH2Cl2, 91%; (t) Ac2O, DMAP, pyridine, 87%; (u) TBAF, THF, 99%; (v) DesseMartin periodinane, pyridine, CH2Cl2, 83%; (w) MeMgBr, THF, 50 (40%), 51 (16%); (x)
K2CO3, MeOH, 49%; (y) TPAP, NMO, MS4A, 53%; (z) KOH, EtOH, rt, 53 (64%), 54 (12%); (aa) KOH, EtOH, 60  C, 52%.

into 12a, 12b was obtained in 65% yield from 9b as a colorless oil: IR
(ATR) 3518, 2921, 1598 cm
1; MS (FABþ) m/z 362 (MþHþ), 344,
304; HRMS m/z calcd for C19H24NO4S: 362.1426, found 362.1421; 1H
NMR (400 MHz, CDCl3) d 7.74 (d, J¼8.3 Hz, 2H), 7.32 (d, J¼8.3 Hz,
2H), 7.21 (t, J¼7.8 Hz, 1H), 6.85e6.77 (m, 3H), 5.57 (dt, J¼15.4,
5.1 Hz, 1H), 5.39 (dt, J¼15.4, 6.8 Hz, 1H), 4.30 (s, 2H), 3.96 (d,
J¼5.1 Hz, 2H), 3.76 (s, 3H), 3.75 (d, J¼6.8 Hz, 2H), 2.44 (s, 3H), 1.11
(br, 1H); 13C NMR (100 MHz, CDCl3) d 159.80 (C), 143.37 (C), 137.79
(C), 137.26 (C), 133.71 (CH), 129.73 (CH2), 129.47 (CH), 127.26
(CH2), 125.72 (CH), 120.75 (CH), 113.79 (CH), 113.38 (CH), 62.67
(CH2), 55.21 (CH3), 50.78 (CH2), 48.73 (CH2), 21.51 (CH3).
4.2.3. N-[(2E)-4-Hydroxy-2-butenyl]-N-(3,4-dimethoxybenzyl)-4-
methylbenzenesulfonamide (12c). According to the conversion of 9a
into 12a, 12c was obtained in 69% yield from 9c as a white amor-
phous: IR (neat) 3522, 1597, 1334 cm
1; EIMS m/z 391 (Mþ), 320,
236; HRMS m/z calcd for C20H25NO5S: 391.1452, found 391.1471; 1H
NMR (270 MHz, CDCl3) d 7.73 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz,
2H), 6.82e6.68 (m, 3H), 5.50 (dt, J¼15.5, 5.2 Hz, 1H), 5.40 (dt,
J¼15.5, 5.9 Hz, 1H), 4.27 (s, 2H), 3.99 (br s, 2H), 3.85 (s, 3H), 3.79 (s,
3H), 3.73 (d, J¼5.9 Hz, 2H), 2.43 (s, 3H); 13C NMR (68 MHz, CDCl3)
d 149.0 (C), 148.5 (C), 143.3 (C), 137.3 (C), 133.7 (CH), 129.6 (CH2),
128.3 (C), 127.1 (CH2), 125.4 (CH), 120.9 (CH), 111.3 (CH), 110.7
(CH), 62.5 (CH2), 55.8 (CH3), 55.7 (CH3), 50.3 (CH2), 48.1 (CH2), 21.4
(CH3).
4.2.4. N-(1,3-Benzodioxol-5-ylmethyl)-N-[(2E)-4-hydroxy-2-
butenyl]-4-methylbenzenesulfonamide (12d). According to the con-
version of 9a into 12a, 12d was obtained in 63% yield from 9d as
white crystals; mp 93e94  C (n-hexane/AcOEt); IR (ATR) 3526,
2907, 1599, 1387 cm
1; EIMS m/z 375 (Mþ), 304, 220; HRMS m/z
calcd for C19H21NO5S: 375.1139, found 375.1115; 1H NMR (270 MHz,
CDCl3) d 7.72 (d, J¼8.0 Hz, 2H), 7.32 (d, J¼8.0 Hz, 2H), 6.77 (d,
J¼1.4 Hz, 1H), 6.72 (d, J¼7.8 Hz, 1H), 6.66 (dd, J¼7.8, 1.4 Hz, 1H), 5.94
(s, 2H), 5.59 (dt, J¼15.3, 5.3 Hz, 1H), 5.38 (dt, J¼15.3, 6.5 Hz, 1H),
4.22 (s, 2H), 3.99 (d, J¼4.6 Hz, 2H), 3.74 (d, J¼6.5 Hz, 2H), 2.44 (s,
3H);13C NMR (68 MHz, CDCl3) d 147.9 (C), 147.2 (C), 143.4 (C), 137.3
(C), 133.7 (CH), 129.8 (C), 129.7 (CH2), 127.2 (CH2), 125.5 (CH),
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
121.9 (CH), 108.9 (CH), 108.0 (CH), 101.1 (CH2), 62.6 (CH2), 50.4
(CH2), 48.3 (CH2), 21.5 (CH3). Anal. Calcd for C19H21NO5S: C, 60.78;
H, 5.64; N, 3.73. Found: C, 61.06; H, 5.72; N, 3.67.
4.2.5. N-Allyl-N-(3,4-dimethoxybenzyl)-4-methylbenzenesulfonamide
(13). To a solution of 9c (2.03 g, 6.30 mmol) in DMF (63 mL) were
added NaH (60% purity, 1.25 g, 31.2 mmol, 5 equiv) and allyl bro-
mide (1.8 mL, 12.6 mmol, 2 equiv) at 0  C. This solution was stirred
for 30 min, then quenched with H2O and extracted with Et2O, and
washed with brine. The extract was dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(3:1) to give 13 (2.10 g, 5.82 mmol, 92%) as a white amorphous: IR
(ATR) 2932, 1594, 1155 cm
1; EIMS m/z 361 (Mþ), 205, 190, 174;
HRMS m/z calcd for C19H23NO4S: 361.1346, found 361.1346; 1H
NMR (270 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H), 7.31 (d, J¼8.2 Hz,
2H), 6.80e6.70 (m, 3H), 5.49 (ddt, J¼16.8, 10.2, 6.5 Hz, 1H), 5.07 (d,
J¼10.2 Hz, 1H), 5.02 (d, J¼16.8 Hz, 1H), 4.28 (s, 2H), 3.86 (s, 3H),
3.80 (s, 3H), 3.74 (d, J¼6.5 Hz, 2H), 2.44 (s, 3H); 13C NMR (68 MHz,
CDCl3) d 149.1 (C), 148.6 (C), 143.2 (C), 137.7 (C), 132.4 (CH), 129.7
(CH2), 128.3 (C), 127.1 (CH2), 120.9 (CH), 119.1 (CH2), 111.4 (CH),
110.7 (CH), 55.8 (CH3), 55.7 (CH3), 50.0 (CH2), 49.1 (CH2), 21.5
(CH3).
4 . 2 . 6 . N - ( 3 - H y d r o x y p ro p yl ) - N - ( 3 , 4 - d i m e t h o x y b e n z yl ) - 4 -
methylbenze-nesulfonamide (14). To a solution of 13 (4.31 g,
11.9 mmol) in THF (120 mL) was added dropwise 9-BBN (0.5 M in
THF, 71.5 mmol, 6 equiv) at 0  C. After being stirred for 20 h at room
temperature, 1 N NaOH (140 mL) and 35% H2O2 (140 mL) were added
to the reaction mixture at 0  C. The reaction mixture was stirred for
30 min, and then extracted with Et2O. The extract was dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with n-
hexane/AcOEt (3:2) to give 14 (3.78 g, 10.0 mmol, 84%) as a white
amorphous: IR (neat) 3546, 1334, 1160; EIMS m/z 379 (Mþ), 224, 193,
179; HRMS m/z calcd for C19H25NO5S: 379.1452, found 379.1482; 1H
NMR (270 MHz, CDCl3) d 7.73 (d, J¼8.2 Hz, 2H), 7.33 (d, J¼8.2 Hz, 2H),
6.80e6.75 (m, 3H), 4.25 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.68e3.47
(m, 2H), 3.23 (t, J¼6.2 Hz, 2H), 2.44 (s, 3H), 2.30 (br s, 1H), 1.44 (dt,
J¼11.8, 6.2 Hz, 2H); 13C NMR (68 MHz, CDCl3) d 149.1 (C), 148.8 (C),
143.4 (C), 136.5 (C), 129.8 (CH2), 128.6 (C), 127.1 (CH2), 120.8 (CH),
111.2 (CH), 110.7 (CH), 58.6 (CH2), 55.8 (CH3), 55.7 (CH3), 52.8 (CH2),
44.8 (CH2), 30.9 (CH2), 21.4 (CH3). Anal. Calcd for C19H25NO5S: C,
60.14; H, 6.64; N, 3.69. Found: C, 59.86; H, 6.77; N, 3.85.
4.2.7. Methyl (2E)-5-[N-(3,4-dimethoxybenzyl)-4-methylphen-
ylsulfonamido]-2-pentenoate (15). To a solution of 14 (1.56 g,
4.11 mol) in CH2Cl2 (100 mL) was added DesseMartin periodinane
(3.49 g, 8.23 mmol) at 0  C under an argon atmosphere. After being
stirred for 1 h, Ph3P]CHCOOMe (2.75 g, 8.23 mmol) was added to
the reaction mixture at room temperature. The reaction mixture was
further stirred for 2 h and quenched with saturated aqueous NaHCO3
and extracted with CH2Cl2. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(4:1) to give 15 (1.51 g, 3.49 mmol, 85%) as a white amorphous: IR
(neat) 1721, 1659, 1597, 1334 cm
1; EIMS m/z 433 (Mþ), 278, 218, 178;
HRMS m/z calcd for C22H27NO6S: 433.1558, found 433.1571; 1H NMR
(270 MHz, CDCl3) d 7.74 (d, J¼8.2 Hz, 2H), 7.34 (d, J¼8.2 Hz, 2H),
6.82e6.74 (m, 3H), 6.67 (dt, J¼15.5, 7.2 Hz, 1H), 6.65 (d, J¼15.5 Hz,
1H), 4.25 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.69 (s, 3H), 3.18 (t,
J¼7.2 Hz, 2H), 2.44 (s, 3H), 2.24 (q, J¼7.2 Hz, 2H); 13C NMR (68 MHz,
CDCl3) d 166.4 (C), 149.2 (C), 148.8 (C), 144.8 (CH), 143.4 (C), 136.6 (C),
129.7 (CH2), 128.2 (C), 127.1 (CH2), 122.7 (CH), 120.6 (CH), 111.1
(CH), 110.7 (CH), 55.8 (CH3), 55.7 (CH3), 52.4 (CH2), 51.4 (CH3), 46.3
(CH2), 31.6 (CH2), 21.4 (CH3).
4127
4.2.8. N-[(3E)-5-Hydroxy-3-pentenyl]-N-(3,4-dimethoxybenzyl)-4-
methylbenzenesulfonamide (16). To a solution of 15 (2.15 g,
4.97 mmol) in CH2Cl2 was added dropwise DIBAH (1.01 M in tolu-
ene, 15.0 mL, 14.9 mmol, 3 equiv) at
78  C under an argon at-
mosphere. This solution was stirred for 1 h, and then quenched
with small amount of H2O. The precipitate was removed by filtra-
tion. The filtrate was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel eluted with n-hexane/AcOEt (2:1) to give 16
(1.89 g, 4.36 mmol, 88%) as an amorphous: IR (neat) 3534, 1597,
1336, 1158 cm
1; EIMS m/z 405 (Mþ), 334, 250, 178, 165; HRMS m/z
calcd for C21H27NO5S 405.1610; found 405.1614; 1H NMR (270 MHz,
CDCl3) d 7.73 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 6.80e6.76 (m,
3H), 5.58e5.35 (m, 2H), 4.25 (s, 2H), 3.98 (t, J¼5.3 Hz, 2H), 3.86 (s,
3H), 3.80 (s, 3H), 3.14 (t, J¼7.2 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J¼7.2 Hz,
2H), 1.58 (t, J¼5.3 Hz, 1H); 13C NMR (68 MHz, CDCl3) d 149.12 (C),
148.67 (C), 143.22 (C), 137.07 (C), 131.37 (CH), 129.66 (CH2), 128.53
(C), 128.47 (CH), 127.09 (CH2), 120.65 (CH), 111.24 (CH), 110.69
(CH), 63.24 (CH2), 55.81 (CH3), 55.75 (CH3), 51.77 (CH2), 47.20 (CH2),
31.19 (CH2), 21.41 (CH3).
4.2.9. N-Allyl-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide
(18a). According to the conversion of 9c into 13, 18a was obtained in
quantitative yield from 17a as a pale yellow oil: IR (neat) 3086 cm
1;
EIMS m/z 317 (Mþ), 253, 212; HRMS m/z calcd for C17H19NO3S:
317.1085, found 317.1109; 1H NMR (400 MHz, CDCl3) d 7.51 (d,
J¼8.3 Hz, 2H), 7.25 (d, J¼8.3 Hz, 2H), 7.16 (t, J¼8.0 Hz, 1H), 6.81 (dd,
J¼8.0, 2.0 Hz, 1H), 6.64 (t, J¼2.0 Hz, 1H), 6.59 (br d, J¼8.0 Hz, 1H), 5.74
(ddt, J¼16.8, 10.5, 6.3 Hz, 1H), 5.08 (d, J¼16.8 Hz, 1H), 5.04 (d,
J¼10.5 Hz, 1H), 4.15 (d, J¼6.3 Hz, 2H), 3.73 (s, 3H), 2.41 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 159.7 (C), 143.4 (C), 140.2 (C), 135.4 (C),
132.7 (CH), 129.3 (CH2), 129.2 (CH), 127.7 (CH2), 120.6 (CH), 118.6
(CH2), 114.7 (CH), 113.5 (CH), 55.2 (CH3), 53.5 (CH2), 21.4 (CH3).
4.2.10. N-Allyl-N-(3,4-dimethoxyphenyl)-4-methylbenzenesulfonamide
(18b). According to the conversion of 9c into 13, 18b was obtained in
quantitative yield from 17b as colorless cubic: mp 68e69  C (AcOEt/
n-hexane); IR (neat) 3020, 1647 cm
1; EIMS m/z 347 (Mþ), 192, 160;
HRMS m/z calcd for C18H21O4NS: 347.1190, found 347.1161; 1H NMR
(270 MHz, CDCl3) d 7.52 (d, J¼8.2 Hz, 2H), 7.25 (d, J¼8.2 Hz, 2H), 6.73
(d, J¼8.2 Hz, 1H), 6.56e6.50 (m, 2H), 5.75 (ddt, J¼16.5, 10.0, 6.6 Hz,
1H), 5.12e5.02 (m, 2H), 4.09e4.17 (d, J¼10.0 Hz, 2H), 3.85 (s, 3H), 3.74
(s, 3H), 2.43 (s, 3H); 13C NMR (68 MHz, CDCl3) d 148.7 (C), 148.6 (C),
143.3 (C), 135.4 (C), 132.9 (CH), 131.8 (C), 129.3 (CH2), 127.8 (CH2),
121.0 (CH), 118.6 (CH2), 112.7 (CH), 110.5 (CH), 55.8 (CH32), 53.9
(CH2), 21.4 (CH3). Anal. Calcd for C18H21O4NS: C, 62.22; H, 6.09; N,
4.03. Found: C, 62.04; H, 6.11; N, 3.88.
4.2.11. N-Allyl-N-(3,5-dimethoxyphenyl)-4-methylbenzenesulfonamide
(18c). According to the conversion of 9c into 13, 18c was obtained in
98% yield from 17c as white needle: mp 83.0e84.0  C (AcOEt/n-
hexane); IR (neat) 3024; 1647 cm
1; EIMS m/z 347 (Mþ), 332, 283,
268, 192; HRMS m/z calcd for C18H21NO4S: 347.1190, found 347.1193;
1
H NMR (270 MHz, CDCl3) d 7.55 (d, J¼8.6 Hz, 2H), 7.26 (d, J¼8.6 Hz,
2H), 6.37 (t, J¼2.3 Hz, 1H), 6.21 (d, J¼2.3 Hz, 2H), 5.75 (ddt, J¼17.0,
10.0, 6.3 Hz, 1H), 5.15e5.03 (m, 2H), 4.12 (d, J¼6.3 Hz, 2H), 3.71 (s,
6H), 2.42 (s, 3H); 13C NMR (68 MHz, CDCl3) d 160.5 (C2), 143.4 (C),
140.9 (C), 135.5 (C), 132.8 (CH), 129.4 (CH2), 127.8 (CH2), 118.7
(CH2), 107.0 (CH2), 100.0 (CH), 55.3 (CH32), 53.6 (CH2), 21.5 (CH3).
Anal. Calcd for C18H21NO4S: C, 62.22; H, 6.09; N, 4.03. Found: C, 62.25;
H, 6.14; N, 4.06.
4.2.12. N-(3-Hydroxypropyl)-N-(3-methoxyphenyl)-4-methylben-
zenesulfonamide (19a). According to the conversion of 13 into 14, 19a
was obtained in 84% yield from 18a as a pale yellow oil: IR (neat)
3530 cm
1; EIMS m/z 335 (Mþ), 290, 271, 226; HRMS m/z calcd for
4128 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
C17H21NO4S: 335.1190, found 335.1173; 1H NMR (400 MHz, CDCl3)
d 7.52 (d, J¼8.3 Hz, 2H), 7.26 (d, J¼8.3 Hz, 2H), 7.21 (t, J¼8.0 Hz, 1H),
6.85 (dd, J¼8.3, 2.0 Hz, 1H), 6.67e6.60 (m, 2H), 3.78 (m, 2H), 3.75 (s,
3H), 3.66 (t, J¼6.0 Hz, 2H), 2.43 (s, 3H), 2.23 (br, 1H), 1.62 (quintet,
J¼6.0 Hz, 2H); 13C NMR (68 MHz, CDCl3) d 160.0 (C), 143.6 (C), 140.2
(C), 135.3 (C), 129.6 (CH), 129.5 (CH2), 127.7 (CH2), 120.7 (CH),
114.9 (CH), 113.8 (CH), 58.8 (CH2), 55.4 (CH3), 47.2 (CH2), 30.6 (CH2),
21.6 (CH3).
4.2.13. N-(3-Hydroxyprop yl)-N-(3,4 -dimethoxyp henyl)-4-
methylbenzenesulfonamide (19b). According to the conversion of 13
into 14, 19b was obtained in 90% yield from 18b as a pale yellow oil:
IR (neat) 3544 cm
1; EIMS m/z 365 (Mþ), 210, 166; HRMS m/z calcd
for C18H23NO5S: 365.1296, found 365.1319; 1H NMR (270 MHz,
CDCl3) d 7.52 (d, J¼8.6 Hz, 2H), 7.27 (d, J¼8.6 Hz, 2H), 6.76 (d,
J¼8.2 Hz, 1H), 6.62e6.52 (m, 2H), 3.87 (s, 3H), 3.80 (q, J¼6.0 Hz, 2H),
3.75 (s, 3H), 3.64 (t, J¼6.0 Hz, 2H), 2.43 (s, 3H), 2.16 (t, J¼6.0 Hz, 1H),
1.63 (quintet, J¼6.0 Hz, 2H); 13C NMR (68 MHz, CDCl3) d 148.9 (C),
148.7 (C), 143.4 (C), 135.1 (C), 131.6 (C), 129.3 (CH2), 127.7 (CH2),
121.0 (CH), 112.4 (CH), 110.7 (CH), 58.8 (CH2), 55.9 (CH3), 55.8 (CH3),
47.5 (CH2), 30.6 (CH2), 21.4 (CH3).
4.2.14. N-(3-Hydroxyprop yl)-N-(3,5 -dimethoxyp henyl)-4-
methylbenzenesulfonamide (19c). According to the conversion of 13
into 14, 19c was obtained in 96% yield from 18c as white needles:
mp 69.0e70.0  C (n-hexane/AcOEt); IR (CHCl3) 3538 cm
1; EIMS
m/z 365 (Mþ), 320, 301, 271, 256; HRMS m/z calcd for C18H23NO5S:
365.1296, found 365.1313; 1H NMR (270 MHz, CDCl3) d 7.54 (d,
J¼8.2 Hz, 2H), 7.26 (d, J¼8.2 Hz, 2H), 6.40 (t, J¼2.3 Hz, 1H), 6.21 (d,
J¼2.3 Hz, 2H), 3.76 (t, J¼6.0 Hz, 2H), 3.71 (s, 6H), 3.62 (t, J¼6.0 Hz,
2H), 2.42 (s, 3H), 1.62 (quintet, J¼6.0 Hz, 2H); 13C NMR (68 MHz,
CDCl3) d 160.7 (C2), 143.5 (C), 140.7 (C), 135.2 (C), 129.4 (CH2),
127.7 (CH2), 107.1 (CH2), 100.2 (CH), 58.8 (CH2), 55.4 (CH32),
47.2 (CH2), 30.5 (CH2), 21.5 (CH3). Anal. Calcd for C18H23NO5S: C,
59.16; H, 6.34; N, 3.83. Found: C, 59.08; H, 6.37; N, 3.71.
4.2.15. Methyl (2E)-5-[N-(3-methoxyphenyl)-4-methylpheny-
lsulfonamido]-2-pentenoate (20a). According to the conversion of 14
into 15, 20a was obtained in 82% yield from 19a as colorless cubic: mp
72.0e73.0  C (n-hexane/AcOEt); IR (CHCl3) 3026, 1725 cm
1; EIMS m/
z 389 (Mþ), 358, 290; HRMS m/z calcd for C20H23O5NS 389.1296,
found 389.1316; 1H NMR (270 MHz, CDCl3) d 7.49 (d, J¼8.0 Hz, 2H),
7.25 (d, J¼8.0 Hz, 2H), 7.20 (t, J¼8.0 Hz, 1H), 6.89e6.80 (m, 2H), 6.62
(t, J¼2.0 Hz, 1H), 6.56 (ddd, J¼8.0, 2.0, 1.0 Hz, 1H), 5.81 (dt J¼16.0,
1.5 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.63 (t, J¼7.1 Hz, 2H), 2.42 (s, 3H),
2.36 (qd, J¼7.0, 1.5 Hz, 2H); 13C NMR (68 MHz, CDCl3) d 166.5 (C),
160.0 (C), 144.7 (CH), 143.6 (C), 139.9 (C), 135.0 (C), 129.6 (CH), 129.4
(CH2), 127.0 (CH2), 123.0 (CH), 120.6 (CH), 114.8 (CH), 114.0 (CH),
55.3 (CH3), 51.5 (CH3), 49.1 (CH2), 31.2 (CH2), 21.5 (CH3). Anal. Calcd
for C20H23NO5S: C, 61.68; H, 5.95; N, 3.60. Found: C, 61.73; H, 6.01; N,
3.43.
4.2.16. Methyl (2E)-5-[N-(3,4-dimethoxyphenyl)-4-methylpheny-
lsulfonamido]-2-pentenoate (20b). According to the conversion
of 14 into 15, 20b was obtained in 83% yield from 19b as a pale
yellow oil: IR (neat) 3026, 1725 cm
1; EIMS m/z 419 (Mþ), 388,
320, 264; HRMS m/z calcd for C21H25NO6S 419.1401, found
419.1423; 1H NMR (270 MHz, CDCl3) d 7.49 (d, J¼8.0 Hz, 2H),
7.26 (d, J¼8.0 Hz, 2H), 6.86 (dt, J¼15.5, 7.0 Hz, 1H), 6.75 (d,
J¼8.2 Hz, 1H), 6.56e6.46 (m, 2H), 5.81 (dt, J¼15.5, 1.3 Hz, 1H),
3.87 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 3.63 (t, J¼7.0 Hz, 2H),
2.42 (s, 3H), 2.36 (qt, J¼7.0, 1.3 Hz, 2H); 13C NMR (68 MHz,
CDCl3) d 166.5 (C), 149.0 (C), 148.9 (C), 144.8 (CH), 143.5 (C),
135.0 (C), 131.4 (C), 129.4 (CH2), 127.9 (CH2), 123.0 (CH),
120.9 (CH), 112.7 (CH), 110.8 (CH), 55.93 (CH3), 55.87 (CH3), 51.5
(CH3), 49.3 (CH2), 31.3 (CH2), 21.5 (CH3).
4.2.17. Methyl (2E)-5-[N-(3,5-dimethoxyphenyl)-4-methylphenyl-
sulfonamido]-2-pentenoate (20c). According to the conversion of
14 into 15, 20c was obtained in 52% yield from 19c as colorless
crystals: mp 98.0e99.0  C (n-hexane/AcOEt); IR (CHCl3) 3024,
1721 cm
1; EIMS m/z 419 (Mþ), 388, 355, 320; HRMS m/z calcd for
C21H25NO6S 419.1401, found 419.1416; 1H NMR (270 MHz, CDCl3)
d 7.52 (d, J¼8.0 Hz, 2H), 7.26 (d, J¼8.0 Hz, 2H), 6.85 (dt, J¼15.0,
7.0 Hz, 1H), 6.40 (t, J¼2.3 Hz, 1H), 6.17 (d, J¼2.3 Hz, 2H), 5.82 (dd,
J¼15.0, 1.0 Hz, 1H), 3.71 (s, 3H), 3.703 (s, 3H), 3.699 (s, 3H), 3.61 (t,
J¼7.0 Hz, 2H), 2.42 (s, 3H) 2.36 (m, 2H); 13C NMR (68 MHz, CDCl3)
d 166.5 (C), 160.7 (C2), 144.7 (CH), 143.6 (C), 140.5 (C), 135.0 (C),
129.4 (CH2), 127.8 (CH2), 123.0 (CH), 107.0 (CH2), 100.4 (CH),
55.4 (CH32), 51.4 (CH3), 49.1 (CH2), 31.2 (CH2), 21.5 (CH3). Anal.
Calcd for C21H25NO6S: C, 60.12; H, 6.01; N, 3.34. Found: C, 59.96; H,
5.98; N, 3.21.
4.2.18. N-[(3E)-5-Hydroxy-3-pentenyl]-N-(3-methoxyphenyl)-4-
methylbenzenesulfonamide (21a). According to the conversion of 15
into 16, 21a was obtained in 85% yield from 20a as a colorless oil: IR
(neat) 3524, 3010 cm
1; EIMS m/z 361 (Mþ), 290, 155; HRMS m/z
calcd for C19H23NO4S 361.1346, found 361.1328; 1H NMR (270 MHz,
CDCl3) d 7.49 (d, J¼8.6 Hz, 2H), 7.24 (d, J¼8.6 Hz, 2H), 7.19 (d,
J¼8.0 Hz, 1H), 6.84 (ddd, J¼8.0, 2.0, 1.0 Hz, 1H), 6.63 (t, J¼2.0 Hz,
1H), 6.58 (ddd, J¼8.0, 2.0, 1.0 Hz, 1H), 5.71e5.52 (m, 2H), 4.06 (br,
2H), 3.75 (s, 3H), 3.57 (t, J¼7.0 Hz, 2H), 2.42 (s, 3H), 2.13e2.25 (m,
2H), 1.40 (br t, 1H); 13C NMR (68 MHz, CDCl3) d 159.9 (C), 143.4 (C),
140.2 (C), 135.3 (C), 131.7 (CH), 129.5 (CH), 129.4 (CH2), 128.5 (CH),
127.7 (CH2), 120.7 (CH), 114.9 (CH), 113.7 (CH), 63.5 (CH2), 55.3
(CH3), 50.2 (CH2), 31.2 (CH2), 21.5 (CH3).
4.2.19. N-[(3E)-5-Hydroxy-3-pentenyl]-N-(3,4-dimethoxyphenyl)-4-
methylbenzenesulfonamide (21b). According to the conversion of 15
into 16, 21b was obtained in 83% yield from 20b as a colorless oil: IR
(neat) 3536, 3014 cm
1; EIMS m/z 391 (Mþ), 373, 320, 236, 165;
HRMS m/z calcd for C20H25NO5S 391.1452, found 391.1431; 1H NMR
(400 MHz, CDCl3) d 7.50 (d, J¼8.0 Hz, 2H), 7.27 (d, J¼8.0 Hz, 2H),
6.75 (d, J¼9.0 Hz, 1H), 6.56e6.50 (m, 2H), 5.72e5.57 (m, 2H), 4.07
(br s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.56 (t, J¼7.0 Hz, 2H), 2.42 (s,
3H), 2.18 (m, 2H) 1.80 (br, 1H); 13C NMR (100 MHz, CDCl3) d 148.8
(C), 148.7 (C), 143.3 (C), 135.2 (C), 131.7 (CH), 131.5 (C), 129.2 (CH2),
128.4 (CH), 127.7 (CH2), 121.0 (CH), 112.6 (CH), 110.7 (CH), 63.3
(CH2), 55.9 (CH3), 55.8 (CH3), 50.4 (CH2), 31.1 (CH2), 21.4 (CH3).
4.2.20. N-[(3E)-5-Hydroxy-3-pentenyl]-N-(3,5-dimethoxyphenyl)-4-
methylbenzenesulfonamide (21c). According to the conversion of 15
into 16, 21c was obtained in 85% yield from 20c as colorless crystal:
mp 73.0e74.0  C (AcOEt/n-hexane); IR (neat) 3402, 3010 cm
1;
EIMS m/z 391 (Mþ), 373, 320, 256; HRMS m/z calcd for C20H25NO5S
391.1452, found 391.1456; 1H NMR (100 MHz, CDCl3) d 7.52 (d,
J¼8.0 Hz, 2H), 7.25 (d, J¼8.0 Hz, 2H), 6.41e6.38 (m, 1H), 6.20e6.18
(m, 2H), 5.68e5.55 (m, 2H), 4.05 (br s, 2H), 3.70 (s, 6H), 3.54 (t,
J¼7.0 Hz, 2H), 2.41 (s, 3H), 2.19 (q, J¼7.0 Hz, 2H), 1.90 (br, 1H); 13C
NMR (400 MHz, CDCl3) d 160.7 (C2) 143.4 (C), 140.7 (C), 135.2 (C),
131.7 (CH), 129.3 (CH2), 128.2 (CH), 127.6 (CH2), 107.1 (CH2),
100.1 (CH), 63.2 (CH2), 55.3 (CH32), 50.1 (CH2), 31.1 (CH2), 21.4
(CH3). Anal. Calcd for C20H25NO5S: C, 61.36; H, 6.44; N, 3.58. Found:
C, 61.41; H, 6.46; N, 3.47.
4.2.21. (2RS,3RS)-N-Benzyl-N-(2,3-epoxy-4-hydroxybutyl)-4-
methylbenzenesulfonamide (22a). To a solution of 12a (1.66 g,
5.01 mmol) in CH2Cl2 (100 mL) was added MCPBA (70% purity,
2.16 g, 8.76 mmol, 1.8 equiv) at 0  C. This solution was stirred for 4 h
at room temperature, then quenched with saturated aqueous
Na2SO3 and extracted with CH2Cl2. The extract was washed with
saturated aqueous NaHCO3, brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by column
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
chromatography on silica gel eluted with n-hexane/AcOEt (2:1) to
give 22a (1.53 g, 4.41 mmol, 88%) as colorless needles: mp 93e94  C
(n-hexane/AcOEt); IR (neat) 3514, 2926, 1601, 1340 cm
1; MS
(SIMSþ) m/z 348 (MþHþ), 332, 314; HRMS m/z calcd for
C18H22NO4S: 348.1268, found 348.1260; 1H NMR (270 MHz, CDCl3)
d 7.74 (d, J¼8.2 Hz, 2H), 7.38e7.24 (m, 7H), 4.49 (d, J¼14.5 Hz, 1H),
4.24 (d, J¼14.5 Hz, 1H), 3.58 (ddd, J¼12.5, 5.6, 2.3 Hz, 1H), 3.36e3.24
(m, 2H), 3.12 (dd, J¼15.1, 5.6 Hz, 1H), 2.92 (td, J¼5.6, 2.3 Hz, 1H), 2.60
(td, J¼4.6, 2.3 Hz, 1H), 2.43 (s, 3H); 13C NMR (68 MHz, CDCl3) d 143.7
(C), 136.2 (C), 136.0 (C), 129.8 (CH2), 128.6 (CH2), 128.3 (CH2),
127.9 (CH), 127.1 (CH2), 61.0 (CH2), 57.6 (CH), 53.6 (CH), 52.8 (CH2),
49.2 (CH2), 21.4 (CH3). Anal. Calcd for C18H21NO4S: C, 62.23; H, 6.09;
N, 4.03. Found: C, 62.08; H, 5.92; N, 3.88.
4.2.22. (2RS,3RS)-N-(2,3-Epoxy-4-hydroxybutyl)-N-(3-methoxy-
benzyl)-4-methylbenzenesulfonamide (22b). According to the con-
version of 12a into 22a, 22b was obtained in 90% yield from 12b as
a pale yellow oil: IR (ATR) 3437, 2917, 1598 cm
1; MS (FABþ) m/z
378 (MþHþ), 304, 222; HRMS m/z calcd for C19H24NO5S: 378.1375,
found 378.1370; 1H NMR (400 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H),
7.34 (d, J¼8.2 Hz, 2H), 7.25e7.20 (m, 1H). 6.88e6.79 (m, 3H), 4.47 (d,
J¼14.7 Hz, 1H), 4.23 (d, J¼14.7 Hz, 1H), 3.77 (s, 3H), 3.65 (dd, J¼12.7,
2.7 Hz, 1H), 3.38 (dd, J¼12.7, 5.2 Hz, 1H), 3.33 (dd, J¼15.1, 5.2 Hz,
1H), 3.13 (dd, J¼15.1, 5.5 Hz, 1H), 2.95 (td, J¼5.5, 2.0 Hz, 1H),
2.67e2.62 (m, 1H), 2.44 (s, 3H), 1.64 (br, 1H); 13C NMR (100 MHz,
CDCl3) d 159.89 (C), 143.70 (C), 137.61 (C), 136.37 (C), 129.87 (CH2),
129.66 (CH), 127.22 (CH2), 120.67 (CH), 113.73 (CH), 113.67 (CH),
61.03 (CH2), 57.67 (CH), 55.22 (CH3), 53.70 (CH), 52.83 (CH2), 49.17
(CH2), 21.51 (CH3).
4.2.23. (2RS,3RS)-N-(2,3-Epoxy-4-hydroxybutyl)-N-(3,4-dimethoxy-
benzyl)-4-methylbenzenesulfonamide(22c). According to the con-
version of 12a into 22a, 22c was obtained in 92% yield from 12c as
an amorphous: IR (neat) 3510, 2938, 1340, 1265 cm
1; EIMS m/z
407 (Mþ), 363, 252; HRMS m/z calcd for C20H25NO6S: 407.1401,
found 407.1417; 1H NMR (270 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H),
7.34 (d, J¼8.2 Hz, 2H), 6.79 (s, 3H), 4.42 (d, J¼14.5 Hz, 1H), 4.24 (d,
J¼14.5 Hz, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.70 (ddd, J¼12.5, 5.2,
2.3 Hz, 1H), 3.43 (ddd, J¼12.5, 6.9, 4.2 Hz, 1H), 3.25 (dd, J¼15.1,
5.2 Hz, 1H), 3.19 (dd, J¼15.1, 5.2 Hz, 1H), 2.96 (td, J¼5.2, 2.3 Hz, 1H),
2.70 (dt, J¼4.2, 2.3 Hz, 1H), 2.44 (s, 3H), 1.69 (dd, J¼6.9, 5.2 Hz, 1H);
13
C NMR (68 MHz, CDCl3) d 149.2 (C), 148.8 (C), 143.6 (C), 136.6 (C),
129.8 (CH2), 128.2 (C), 127.2 (CH2), 121.0 (CH), 111.3 (CH), 110.8
(CH), 61.0 (CH2), 57.4 (CH), 55.9 (CH3), 55.8 (CH3), 53.7 (CH), 52.5
(CH2), 48.6 (CH2), 21.5 (CH3).
4.2.24. (2RS,3RS)-N-(Benzo[1,3]dioxol-5-yl-methyl)-N-(2,3-epoxy-4-
hydroxybutyl)-4-methylbenzenesulfonamide (22d). According to the
conversion of 12a into 22a, 22d was obtained in 81% yield from 12d
as an amorphous; IR (ATR) 3484, 2922, 1597, 1160 cm
1; EIMS m/z
391 (Mþ), HRMS m/z calcd for C19H21NO6S: 391.1088, found
391.1084; 1H NMR (270 MHz, CDCl3) d 7.73 (d, J¼8.2 Hz, 2H), 7.33 (d,
J¼8.2 Hz, 2H), 6.80 (s, 1H), 6.73 (s, 2H), 5.94 (s, 2H), 4.36 (d,
J¼14.5 Hz, 1H), 4.20 (d, J¼14.5 Hz, 1H), 3.72 (dd, J¼12.5, 2.3 Hz, 1H),
3.44 (dd, J¼12.5, 4.4 Hz, 1H), 3.22 (dd, J¼5.3, 1.9 Hz, 1H), 2.94 (td,
J¼5.3, 2.3 Hz, 1H), 2.70 (td, J¼4.4, 2.3 Hz, 1H), 2.44 (s, 3H); 13C NMR
(68 MHz, CDCl3) d 148.1 (C), 147.5 (C), 143.7 (C), 136.6 (C), 129.9
(CH2), 129.7 (C), 127.2 (CH2), 122.0 (CH), 108.9 (CH), 108.1 (CH),
101.2 (CH2), 61.1 (CH2), 57.5 (CH), 53.7 (CH), 52.5 (CH2), 48.8 (CH2),
21.5 (CH3).
4.2.25. (3RS,4RS)-N-(3,4-Epoxy-5-hydroxypentyl)-N-(3,4-
dimethoxybenzyl)-4-methylbenzenesulfonamide (23). According to
the conversion of 12a into 22a, 23 was obtained in 93% yield from
16 as a white amorphous: IR (neat) 3534, 1597, 1336, 1158 cm
1;
EIMS m/z 405 (Mþ), 334, 250, 178; HRMS m/z calcd for
4129
C21H27NO5S: 405.1610, found 405.1614; 1H NMR (270 MHz, CDCl3)
d 7.73 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 6.80e6.76 (m, 3H),
5.58e5.35 (m, 2H), 4.25 (s, 2H), 3.98 (t, J¼5.3 Hz, 1H), 3.86 (s, 3H),
3.80 (s, 3H), 3.14 (t, J¼7.2 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J¼7.2 Hz,
2H), 1.58 (t, J¼5.3 Hz, 1H); 13C NMR (68 MHz, CDCl3) d 149.1 (C),
148.7 (C), 143.2 (C), 137.0 (C), 131.4 (CH), 129.7 (CH2), 128.5 (C),
128.4 (CH), 127.1 (CH2), 120.6 (CH), 111.2 (CH), 110.7 (CH), 63.2
(CH2), 55.8 (CH3), 55.7 (CH3), 51.8 (CH2), 47.2 (CH2), 31.2 (CH2), 21.4
(CH3).
4 . 2 . 2 6 . ( 3 R S , 4 R S ) - N - ( 3 , 4 - E p o x y- 5 - hy d r o x y p e n t yl ) - N - ( 3 -
methoxyphenyl)-4-methylbenzenesulfonamide (24a). According to
the conversion of 12a into 22a, 24a was obtained in 87% yield from
21a as a colorless oil: IR (neat) 3460 cm
1; EIMS m/z 377 (Mþ), 290,
155; HRMS m/z calcd for C19H23NO5S 377.1296, found 377.1296; 1H
NMR (270 MHz, CDCl3) d 7.49 (d, J¼8.3 Hz, 2H), 7.26 (d, J¼8.3 Hz,
2H), 7.21 (t, J¼8.0 Hz, 1H), 6.85 (ddd, J¼8.0, 2.0, 1.0 Hz, 1H), 6.63 (t,
J¼2.0 Hz, 1H), 6.61 (ddd, J¼8.0, 2.0, 1.0 Hz, 1H), 3.83 (m, 1H), 3.75 (s,
3H), 3.75e3.60 (m, 3H), 3.04 (td, J¼6.0, 2.0 Hz, 1H), 2.93e2.90 (m,
1H), 2.42 (s, 3H), 2.10e1.92 (m, 1H), 1.84e1.62 (m, 2H); 13C NMR
(68 MHz, CDCl3) d 160.0 (C), 143.6 (C), 140.0 (C), 134.9 (C), 129.6
(CH), 129.4 (CH2), 127.7 (CH2), 120.5 (CH), 114.7 (CH), 113.8 (CH),
61.8 (CH2), 58.2 (CH), 55.3 (CH3), 53.9 (CH), 47.9 (CH2), 30.6 (CH2),
21.5 (CH3).
4.2.27. (3RS,4RS)-N -(3,4-Epoxy-5-hydroxypentyl)-N-(3, 4-
dimethoxyphenyl)-4-methylbenzenesulfonamide (24b). According to
the conversion of 12a into 22a, 24b was obtained in 87% yield from
21b as a colorless oil: IR (neat) 3532 cm
1; EIMS m/z 407 (Mþ), 307,
152; HRMS m/z calcd for C20H25NO6S 407.1401, found 407.1373; 1H
NMR (270 MHz, CDCl3) d 7.50 (d, J¼8.3 Hz, 2H), 7.26 (d, J¼8.3 Hz,
2H), 6.76 (d, J¼8.5 Hz, 1H), 6.59e6.54 (m, 2H), 3.87 (s, 3H), 3.83 (m,
1H), 3.75 (s, 3H), 3.74e3.59 (m, 3H), 3.06 (td, J¼6.0, 2.0 Hz, 1H), 2.93
(m, 1H), 2.43 (s, 3H), 1.96 (br, 1H), 1.82e1.62 (m, 2H); 13C NMR
(68 MHz, CDCl3) d 149.0 (C), 148.8 (C), 143.5 (C), 134.9 (C), 131.5 (C),
129.4 (CH2), 127.8 (CH2), 120.9 (CH), 112.4 (CH), 110.8 (CH), 61.8
(CH2), 58.2 (CH), 55.92 (CH3), 55.89 (CH3), 54.0 (CH), 48.2 (CH2),
30.6 (CH2), 21.5 (CH3).
4.2.28. (3RS, 4RS)-N-(3,4-Epoxy-5-hydroxypentyl)-N-(3,5-
dimethoxyphenyl)-4-methylbenzenesulfonamide(24c). According to
the conversion of 12a into 22a, 24c was obtained in 59% yield from
21c as a pale yellow oil: IR (neat) 3508 cm
1; EIMS m/z 407 (Mþ),
391, 375, 343, 320, 256; HRMS m/z calcd for C20H25NO6S 407.1401,
found 407.1419; 1H NMR (270 MHz, CDCl3) d 7.53 (d, J¼8.2 Hz, 2H),
7.26 (d, J¼8.2 Hz, 2H), 6.40 (t, J¼2.0 Hz, 1H), 6.21 (d, J¼2.0 Hz, 2H),
3.89e3.55 (m, 4H), 3.72 (s, 6H), 3.04 (td, J¼6.0, 2.0 Hz, 1H), 2.93 (m,
1H), 2.42 (s, 3H), 1.97 (br, 1H), 1.86e1.61 (m, 2H); 13C NMR (68 MHz,
CDCl3) d 160.8 (C2), 143.6 (C), 140.7 (C), 135.0 (C), 129.4 (CH2),
127.8 (CH2), 107.0 (CH2), 100.2 (CH), 61.8 (CH2), 58.2 (CH), 55.4
(CH32), 54.0 (CH), 47.9 (CH2), 30.6 (CH2), 21.5 (CH3).
4.2.29. Methyl (2E,4RS,5RS)-6-(N-benzyl-4-methylbenzenesu-
lfonamido)-4,5-epoxy-2-hexenoate (25a). According to the conver-
sion of 14 into 15, 25a was obtained in 84% yield from 22a as a col-
orless oil: IR (neat) 2956, 1725, 1661, 1601 cm
1; MS (SIMSþ) m/z 402
(MþHþ), 369, 274, 185; HRMS m/z calcd for C21H24NO5S: 402.1374,
found 402.1398; 1H NMR (270 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H),
7.35 (d, J¼8.2 Hz, 2H), 7.35e7.25 (m, 5H), 6.37 (dd, J¼15.5, 6.5 Hz, 1H),
5.92 (d, J¼15.5 Hz, 1H), 4.50 (d, J¼14.5 Hz, 1H), 4.23 (d, J¼14.5 Hz,
1H), 3.73 (s, 3H), 3.35 (dd, J¼15.5, 4.9 Hz, 1H), 3.11 (dd, J¼15.5, 5.9 Hz,
1H), 2.88e2.81 (m, 2H), 2.45 (s, 3H); 13C NMR (68 MHz, CDCl3)
d 165.73 (C), 143.76 (C), 143.20 (CH), 136.24 (C), 135.78 (C), 129.90
(CH2), 128.72 (CH2), 128.46 (CH2), 128.08 (CH), 127.14 (CH2),
123.88 (CH), 58.69 (CH), 55.51 (CH), 52.95 (CH2), 51.68 (CH3), 49.05
(CH2), 21.48 (CH3).
4130 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
4.2.30. Methyl (2E,4RS,5RS)-4,5-epoxy-6-[N-(3-methoxybenzyl)-4-
methylbenzenesulfonamido]-2-hexenoate (25b). According to the
conversion of 14 into 15, 25b was obtained in 80% yield from 22b as
white needles: mp 79e80  C (hexane/AcOEt); IR (ATR) 2951,
1713 cm
1; EIMS m/z 431 (Mþ), 304, 276; HRMS m/z calcd for
C22H25NO6S: 431.1403, found 431.1428; 1H NMR (CDCl3) d 7.75 (d,
J¼8.3 Hz, 2H), 7.35 (d, J¼8.3 Hz, 2H), 7.23 (t, J¼7.5 Hz, 1H),
6.98e6.79 (m, 3H), 6.38 (dd, J¼15.5, 6.9 Hz, 1H), 5.93 (d, J¼15.5 Hz,
1H), 4.49 (d, J¼14.5 Hz, 1H), 4.17 (d, J¼14.5 Hz, 1H), 3.76 (s, 3H), 3.74
(s, 3H), 3.38 (dd, J¼15.2, 4.6 Hz, 1H), 3.08 (J¼15.2, 5.6 Hz, 1H),
2.93e2.83 (m, 2H), 2.45 (s, 3H); 13C NMR (68 MHz, CDCl3) d 165.75
(C), 160.00 (C), 143.78 (C), 143.20 (CH), 137.41 (C), 136.39 (C), 129.93
(CH2), 129.73 (CH), 127.20 (CH2), 123.98 (CH), 120.70 (CH),
113.89 (CH), 113.71 (CH), 58.78 (CH), 55.67 (CH), 55.14 (CH3), 52.99
(CH2), 51.69 (CH3), 49.12 (CH2), 21.49 (CH3). Anal. Calcd for
C22H25NO6S: C, 61.23; H, 5.85; N, 3.25. Found: C, 61.32; H, 5.90; N,
3.12.
4.2.31. Methyl (2E,4RS,5RS)-4,5-epoxy-6-[N-(3,4-dimethoxybenzyl)-
4-methylbenzenesulfonamido]-2-hexenoate (25c). According to the
conversion of 14 into 15, 25c was obtained in 92% yield from 22c as
an amorphous: IR (neat) 2956, 1725, 1661, 1597 cm
1; EIMS m/z 461
(Mþ), 363, 321, 306; HRMS m/z calcd for C23H27NO7S: 461.1507,
found 461.1523; 1H NMR (270 MHz, CDCl3) d 7.75 (d, J¼8.2 Hz, 2H),
7.35 (d, J¼8.2 Hz, 2H), 6.78 (s, 3H), 6.42 (dd, J¼15.5, 6.9 Hz, 1H), 5.96
(d, J¼15.5 Hz, 1H), 4.44 (d, J¼14.5 Hz, 1H), 4.19 (d, J¼14.5 Hz, 1H),
3.87 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.32 (dd, J¼15.1, 4.9 Hz, 1H),
3.16 (dd, J¼15.1, 5.2 Hz, 1H), 2.94e2.83 (m, 2H), 2.45 (s, 3H); 13C
NMR (68 MHz, CDCl3) d 165.65 (C), 149.23 (C), 148.88 (C), 143.68 (C),
143.19 (CH), 136.40 (C), 129.86 (CH2), 127.93 (C), 127.08 (CH2),
123.98 (CH), 120.97 (CH), 111.27 (CH), 110.77 (CH), 58.78 (CH), 55.77
(CH3), 55.70 (CH3), 55.43 (CH), 52.63 (CH2), 51.65 (CH3), 48.60
(CH2), 21.42 (CH3).
4.2.32. Methyl (2E,4RS,5RS)-6-[N-(benzo[1,3]dioxol-5-yl-methyl)-4-
methylbenzenesulfonamido]-4,5-epoxy-2-hexenoate
(25d). According to the conversion of 14 into 15, 25d was obtained
in 65% yield from 22d as an amorphous: IR (neat) 1725, 1344,
1245 cm
1; EIMS m/z 445 (Mþ), 347, 318, 290; HRMS m/z calcd for
C22H23NO7S: 445.1193, found 445.1192; 1H NMR (270 MHz, CDCl3)
d 7.73 (d, J¼8.5 Hz, 2H), 7.34 (d, J¼7.9 Hz, 2H), 6.81 (d, J¼0.9 Hz, 1H),
6.76e6.64 (m, 2H), 6.39 (dd, J¼15.8, 6.9 Hz, 1H), 5.96 (s, 2H), 5.95 (d,
J¼15.8 Hz, 1H), 4.42 (d, J¼14.2 Hz, 1H), 4.09 (d, J¼14.2 Hz, 1H), 3.74
(s, 3H), 3.37 (dd, J¼15.2, 4.6 Hz, 1H), 3.08 (dd, J¼15.2, 5.6 Hz, 1H),
2.92e2.83 (m, 2H), 2.45 (s, 3H); 13C NMR (68 MHz, CDCl3) d 165.72
(C), 148.14 (C), 147.56 (C), 143.78 (C), 143.25 (CH), 136.25 (C), 129.92
(CH2), 129.56 (C), 127.10 (CH2), 123.99 (CH), 121.87 (CH), 108.83
(CH), 108.08 (CH), 101.22 (CH2), 58.78 (CH), 55.70 (CH), 52.83 (CH2),
51.70 (CH3), 48.95 (CH2), 21.49 (CH3).
4.2.33. Methyl (2E,4RS,5RS)-4,5-epoxy-7-[N-(3,4-dimethoxybenzyl)-
4-methylbenzenesulfonamido]-2-heptenoate (26). According to the
conversion of 14 into 15, 26 was obtained in 85% yield from 23 as
a white amorphous: IR (neat) 1719, 1597 cm
1; EIMS m/z 475
(Mþ), 419, 377, 320; HRMS m/z calcd for C24H29NO7S: 475.1663,
found 475.1646; 1H NMR (270 MHz, CDCl3) d 7.78 (d, J¼8.2 Hz,
2H), 7.34 (d, J¼8.2 Hz, 2H), 6.77 (s, 3H), 6.58 (dd, J¼15.8, 6.9 Hz,
1H), 6.06 (d, J¼15.8 Hz, 1H), 4.28 (d, J¼14.5 Hz, 1H), 4.21 (d,
J¼14.5 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H), 3.33e3.13
(m, 2H), 3.06 (dd, J¼6.9, 1.6 Hz, 1H), 2.69 (ddd, J¼6.5, 4.9, 1.6 Hz,
1H), 2.44 (s, 3H), 1.83e1.68 (m, 1H), 1.62e1.47 (m, 1H); 13C NMR
(68 MHz, CDCl3) d 165.91 (C), 149.22 (C), 148.82 (C), 144.24 (CH),
143.45 (C), 136.51 (C), 129.77 (CH2), 128.33 (C), 127.14 (CH2),
123.32 (CH), 120.79 (CH), 111.25 (CH), 110.76 (CH), 58.84 (CH2),
55.99 (CH), 55.81 (CH3), 55.77 (CH3), 52.49 (CH2), 51.65 (CH3),
44.73 (CH2), 31.39 (CH2), 21.44 (CH3).
4.2.34. Methyl (2E,4RS,5RS)-4,5-epoxy-7-[N-(3-methoxyphenyl)-4-
methylbenzenesulfonamido]-2-heptenoate (27a). According to the
conversion of 14 into 15, 27a was obtained in 66% yield from 24a as
a pale yellow oil: IR (neat) 3026, 1725 cm
1; EIMS m/z 431 (Mþ),
290, 155; HRMS m/z calcd for C22H25NO6S 431.1401, found 431.1402;
1
H NMR (400 MHz, CDCl3) d 7.49 (d, J¼8.3 Hz, 2H), 7.25 (d, J¼8.3 Hz,
2H), 7.20 (t, J¼8.0 Hz, 1H), 6.84 (ddd, J¼8.0, 2.0, 1.0 Hz, 1H),
6.66e6.57 (m, 3H), 6.10 (dd, J¼15.6, 1.0 Hz, 1H), 3.74 (s, 6H),
3.74e3.59 (m, 2H), 3.17 (dd, J¼7.0, 2.0 Hz, 1H), 2.92 (ddd, J¼6.3, 5.1,
2.0 Hz, 1H), 2.42 (s, 3H), 1.88e1.68 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 165.9 (C), 160.0 (C), 144.2 (CH), 143.6 (C), 140.0 (C), 134.8
(C), 129.6 (CH), 129.4 (CH2), 127.7 (CH2), 123.5 (CH), 120.4 (CH),
114.7 (CH), 113.7 (CH), 58.8 (CH), 56.1 (CH), 55.3 (CH3), 51.7 (CH3),
47.4 (CH2), 31.1 (CH2), 21.5 (CH3).
4.2.35. Methyl (2E,4RS,5RS)-4,5-epoxy-7-[N-(3,4-dimethoxyphenyl)-
4-methylbenzenesulfonamido]-2-heptenoate (27b). According to the
conversion of 14 into 15, 27b was obtained in 62% yield from 24b as
a pale yellow oil: IR (neat) 3026, 1725 cm
1; EIMS m/z 461 (Mþ),
363, 320, 306; HRMS m/z calcd for C23H27NO7S 461.1507, found
461.1523; 1H NMR (270 MHz, CDCl3) d 7.49 (d, J¼8.3 Hz, 2H), 7.26 (d,
J¼8.3 Hz, 2H), 6.76 (d, J¼9.0 Hz, 1H), 6.64 (dd, J¼15.6, 7.0 Hz, 1H),
6.57e6.52 (m, 2H), 6.11 (d, J¼15.6 Hz, 1H), 3.87 (s, 3H), 3.75 (s, 3H),
3.74 (s, 3H), 3.73e3.58 (m, 2H), 3.19 (dd, J¼7.0, 1.7 Hz, 1H), 2.93 (m,
1H), 2.43 (s, 3H), 1.87 (m, 1H), 1.72 (m, 1H); 13C NMR (68 MHz,
CDCl3) d 166.0 (C), 149.0 (C), 148.9 (C), 144.3 (CH), 143.6 (C), 134.9
(C), 131.6 (C), 129.4 (CH2), 127.9 (CH2), 123.6 (CH), 120.9 (CH),
112.4 (CH), 110.8 (CH), 58.9 (CH), 56.2 (CH), 56.0 (CH3), 55.9 (CH3),
51.7 (CH3), 47.8 (CH2), 31.2 (CH2), 21.5 (CH3).
4.2.36. Methyl (2E,4RS,5RS)-4,5-epoxy-7-[N-(3,5-dimethoxyphenyl)-
4-methylbenzenesulfonamido]-2-heptenoate (27c). According to the
conversion of 14 into 15, 27c was obtained in 74% yield from 24c as
a pale yellow oil: IR (neat) 3026, 1725 cm
1; EIMS m/z 461 (Mþ),
429, 397; HRMS m/z calcd for C23H27NO7S 461.1507, found
461.1522; 1H NMR (270 MHz, CDCl3) d 7.52 (d, J¼8.0 Hz, 2H), 7.26 (d,
J¼8.0 Hz, 2H), 6.62 (dd, J¼16.0, 7.0 Hz, 1H), 6.39 (t, J¼2.0 Hz, 1H),
6.19 (d, J¼2.0 Hz, 2H), 6.10 (dd, J¼16.0, 0.7 Hz, 1H), 3.74 (s, 3H), 3.71
(s, 6H), 3.75e3.55 (m, 2H), 3.19 (dd, J¼7.2, 2.0 Hz, 1H), 2.92 (ddd,
J¼6.3, 5.3, 2.0 Hz, 1H), 2.42 (s, 3H), 1.93e1.65 (m, 2H); 13C NMR
(68 MHz, CDCl3) d 166.0 (C), 160.8 (C2), 144.3 (CH), 143.7 (C), 140.7
(C), 134.9 (C), 129.4 (CH2), 127.9 (CH2), 123.6 (CH), 106.9 (CH2),
100.2 (CH), 58.9 (CH), 56.2 (CH), 55.5 (CH32), 51.8 (CH3), 47.5
(CH2), 31.1 (CH2), 21.6 (CH3).
4.3. General procedure for intramolecular FriedeleCrafts
reaction
To a solution of vinyloxirane was added Lewis acid (BF3$Et2O or
TMSOTf, 0.5 equiv) at
30  C or 0  C under an argon atmosphere.
The mixture was stirred for adequate time (20 mine3 h), then
quenched with saturated aqueous NaHCO3, and extracted with
CH2Cl2. The extract was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel eluted with n-hexane/AcOEt.
4.3.1. Methyl (2E,4SR)-4-phenyl-4-[(5RS)-3-tosyloxazolidin-5-yl]-2-
butenoate (28a). Amorphous: IR (KBr) 2956, 1723, 1657,
1597 cm
1; MS (SIMSþ) m/z 402 (MþHþ), 370, 185; HRMS m/z calcd
for C21H24NO5S: 402.1373, found 402.1354; 1H NMR (270 MHz,
CDCl3) d 7.71 (d, J¼8.2 Hz, 2H), 7.37 (d, J¼8.2 Hz, 2H), 7.34e7.22 (m,
3H), 7.03 (dd, J¼7.9, 1.3 Hz, 2H), 7.01 (dd, J¼15.8, 7.5 Hz, 1H), 5.65
(dd, J¼15.8, 1.3 Hz, 1H), 5.07 (d, J¼6.2 Hz, 1H), 4.84 (d, J¼6.2 Hz, 1H),
4.06 (ddd, J¼9.2, 7.5, 6.5 Hz, 1H), 3.68 (s, 3H), 3.29 (dd, J¼11.5,
6.5 Hz, 1H), 3.02 (dd, J¼9.2, 7.5 Hz, 1H), 2.97 (dd, J¼11.5, 7.5 Hz, 1H),
2.48 (s, 3H); 13C NMR (68 MHz, C6D6) d 166.30 (C), 147.54 (CH),
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
144.22 (C), 138.20 (C), 134.88 (C), 129.99 (CH2), 129.29 (CH2),
128.34 (CH2), 128.21 (CH2), 127.84 (CH), 122.95 (CH), 80.92
(CH2), 79.76 (CH2), 51.79 (CH3), 51.13 (CH), 50.07 (CH2), 21.17 (CH3).
4 . 3 . 2 . M e t hyl ( 2 E , 4 S R ) - 4 - ( 3 - m e t h o x y p h e nyl ) - 4 - [ ( 5 R S ) - 3 -
tosyloxazolidin-5-yl]-2-butenoate (28b). Pale yellow oil: IR (neat)
2956, 1723, 1659, 1601; EIMS m/z 431 (Mþ), 400, 226; HRMS m/z
calcd for C22H25NO6S: 431.1401, found 431.1422; 1H NMR (400 MHz,
CDCl3) d 7.72 (d, J¼8.3 Hz, 2H), 7.37 (d, J¼8.3 Hz, 2H), 7.23 (t,
J¼7.8 Hz, 1H), 6.99 (dd, J¼15.6, 7.3 Hz, 1H), 6.81 (dd, J¼7.8, 2.4 Hz,
1H), 6.60 (d, J¼7.8 Hz, 1H), 6.55 (d, J¼2.4 Hz, 1H), 5.65 (d, J¼15.6 Hz,
1H), 5.06 (d, J¼5.9 Hz, 1H), 4.83 (d, J¼5.9 Hz, 1H), 4.04 (dd, J¼16.1,
7.3 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.31 (dd, J¼12.7, 6.8 Hz, 1H),
3.03e2.96 (m, 2H), 2.48 (s, 3H); 13C NMR (68 MHz, CDCl3) d 166.42
(C), 160.06 (C), 146.93 (CH), 144.45 (C), 138.88 (C), 134.12 (C), 130.27
(CH), 129.92 (CH2), 127.93 (CH2), 122.69 (CH), 120.17 (CH),
114.30 (CH), 112.67 (CH), 80.87 (CH2), 79.51 (CH), 55.21 (CH3), 51.78
(CH), 51.55 (CH3), 50.04 (CH2), 21.61 (CH3).
4.3.3. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-8-methoxy-2-tosyl-2,3,4,5-
tetrahydro-1H-2-benzazepin-5-yl]-propenoate (29b). White crystals:
mp 149  C (n-hexane/AcOEt); IR (KBr) 3528, 1717, 1651 cm
1; EIMS
m/z 431 (Mþ), 413, 276, 218; HRMS m/z calcd for C22H25NO6S:
431.1403, found 431.1426; 1H NMR (400 MHz, CDCl3) d 7.69 (d,
J¼8.3 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H), 7.09 (d, J¼8.3 Hz, 1H), 7.06 (dd,
J¼15.6, 4.9 Hz, 1H), 6.83 (d, J¼2.9 Hz, 1H), 6.80 (dd, J¼8.3, 2.9 Hz, 1H),
5.50 (d, J¼15.6 Hz, 1H), 4.61 (d, J¼15.2 Hz, 1H), 4.15e4.08 (m, 1H),
4.02e3.96 (m, 1H), 3.91 (d, J¼15.2 Hz, 1H), 3.82 (s, 3H), 3.67 (s, 3H),
3.11 (d, J¼12.7 Hz, 1H), 2.48 (d, J¼10.3 Hz, 1H), 2.44 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 166.49 (C), 159.31 (C), 146.50 (CH), 143.82 (C),
137.94 (C), 135.92 (C), 134.00 (CH), 129.93 (CH2), 127.12 (CH2),
127.04 (C), 122.92 (CH), 116.02 (CH), 113.31 (CH), 69.15 (CH), 55.38
(CH3), 54.14 (CH), 53.80 (CH2), 53.25 (CH2), 51.62 (CH3), 21.52 (CH3).
Anal. Calcd for C22H25NO6S: C, 61.24; H, 5.84; N, 3.25. Found: C, 61.20;
H, 5.91; N, 3.19.
4.3.4. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-6-methoxy-2-tosyl-2,3,4,5-
tetrahydro-1H-2-benzazepin-5-yl]-propenoate (30b). White crystals:
mp 201  C (MeOH); IR (ATR) 3504, 2922, 1705, 1586 cm
1; MS
(SIMSþ) m/z 432 (MþHþ), 414, 382, 316; HRMS m/z calcd for
C22H26NO6S: 432.1479, found 432.1471; 1H NMR (270 MHz, CDCl3)
d 7.69 (d, J¼8.3 Hz, 2H), 7.31 (d, J¼8.3 Hz, 2H), 7.25 (t, J¼7.9 Hz, 1H),
7.01 (dd, J¼15.8, 4.3 Hz, 1H), 6.93 (d, J¼7.9 Hz, 1H), 6.90 (d, J¼7.9 Hz,
1H), 5.41 (dd, J¼15.8, 2.6 Hz, 1H), 5.06e4.98 (m, 1H), 4.61 (dd, J¼14.8,
2.0 Hz, 1H), 4.28e4.19 (m, 1H), 3.99 (br d, J¼12.8 Hz, 1H), 3.83 (d,
J¼10.2 Hz, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 3.09 (d, J¼12.8 Hz, 1H), 2.44
(d, J¼9.9 Hz, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) d 166.61 (C),
159.12 (C), 146.29 (CH), 143.76 (C), 138.70 (C), 135.92 (C), 129.93
(CH2), 129.11 (CH), 127.11 (CH2), 123.45 (C), 122.34 (CH), 121.84
(CH), 111.13 (CH), 68.65 (CH), 56.16 (CH3), 53.75 (CH2), 53.56 (CH2),
51.54 (CH3), 44.12 (CH2), 21.52 (CH3).
4.3.5. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-7-methoxy-2-tosyl-2,3,4,5-
tetrahydro-1H-2-benzazepin-5-yl]-propenoate (31b). Amorphous: IR
(ATR) 3473, 2922, 1703, 1584 cm
1; MS (SIMSþ) m/z 432 (MþHþ),
400, 369, 278; HRMS m/z calcd for C22H26NO6S: 432.1479, found
432.1473; 1H NMR (400 MHz, CDCl3) d 7.69 (d, J¼8.2 Hz, 2H), 7.32 (d,
J¼8.2 Hz, 2H), 7.21 (d, J¼8.3 Hz, 1H), 7.21 (d, J¼8.3 Hz, 1H), 7.05 (dd,
J¼15.8, 4.9 Hz, 1H), 6.78 (d, J¼8.3 Hz, 1H), 6.74 (d, J¼2.4 Hz, 1H), 5.53
(dd, J¼15.8, 2.4 Hz,1H), 4.64 (dd, J¼14.6,1.4 Hz,1H), 4.01e3.96 (m,1H),
3.93 (d, J¼14.2 Hz,1H), 3.88 (d, J¼14.6 Hz,1H), 3.79 (s, 3H), 3.68 (s, 3H),
3.12 (dd, J¼14.2, 1.4 Hz, 1H), 2.56 (d, J¼10.3 Hz, 1H), 2.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 166.40 (C), 159.64 (C), 145.73 (CH), 143.74 (C),
137.08 (C), 135.96 (C), 131.25 (CH), 129.90 (CH2), 128.67 (C), 127.08
(CH2), 123.14 (CH), 118.86 (CH), 112.40 (CH), 69.34 (CH), 55.28 (CH3),
54.98 (CH), 53.08 (CH2), 52.96 (CH2), 51.62 (CH3), 21.50 (CH3).
4131
4.3.6. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-9-methoxy-2-tosyl-2,3,4,5-
tetrahydro-1H-2-benzazepin-5-yl]-propenoate (32b). Amorphous: IR
(ATR) 3351, 2922, 1659 cm
1; MS (SIMSþ) m/z 432 (MþHþ), 400, 369,
277; HRMS m/z calcd for C22H26NO6S: 432.1479, found 432.1507; 1H
NMR (400 MHz, CDCl3) d 7.74 (d, J¼8.3 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H),
7.22 (t, J¼8.3 Hz, 1H), 7.07 (dd, J¼16.1, 5.4 Hz, 1H), 6.87 (d, J¼8.3 Hz,
1H), 6.78 (d, J¼8.3 Hz, 1H), 5.54 (d, J¼16.1 Hz, 1H), 5.35 (d, J¼14.2 Hz,
1H), 4.17e4.09 (m, 1H), 4.08e4.02 (m, 1H), 3.95 (d, J¼14.2 Hz, 1H),
3.87 (s, 3H), 3.69e3.67 (m, 1H), 3.68 (s, 3H), 3.11 (dd, J¼14.2, 1.5 Hz,
1H), 2.47 (d, J¼9.8 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 166.51 (C), 157.03 (C), 146.05 (CH), 143.62 (C), 137.48 (C), 135.83 (C),
129.81 (CH2), 129.19 (CH), 128.18 (C), 127.29 (CH2), 122.99 (CH),
119.49 (CH), 111.14 (CH), 69.47 (CH), 56.26 (CH3), 54.72 (CH), 53.15
(CH2), 51.64 (CH3), 44.42 (CH2), 21.55 (CH3).
4.3.7. Methyl (2E,4SR)-4-(3,4-dimethoxyphenyl)-4-[(5RS)-3-
tosyloxazolidin-5-yl]-2-butenoate (28c). Amorphous: IR (neat)
2956, 1723, 1657, 1597 cm
1; EIMS m/z 461 (Mþ), 276, 262, 155;
HRMS m/z calcd for C23H27NO7S: 461.1507, found 461.1505; 1H NMR
(270 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.36 (d, J¼8.2 Hz, 2H), 7.00
(dd, J¼15.5, 7.5 Hz, 1H), 6.81 (d, J¼8.2 Hz, 1H), 6.59 (dd, J¼8.2, 1.6 Hz,
1H), 6.53 (d, J¼1.6 Hz, 1H), 5.67 (dd, J¼15.5, 1.3 Hz, 1H), 5.06 (d,
J¼6.2 Hz, 1H), 4.84 (d, J¼6.2 Hz, 1H), 4.01 (ddd, J¼8.5, 7.3, 6.9 Hz,
1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.69 (s, 3H), 3.31 (dd, J¼11.5, 6.6 Hz,
1H), 3.07e2.96 (m, 2H), 2.47 (s, 3H); 13C NMR (68 MHz, CDCl3)
d 166.42 (C), 149.31 (C), 148.62 (C), 147.15 (CH), 144.35 (C), 134.07
(C), 129.80 (CH2), 129.76 (C), 127.83 (CH2), 122.39 (CH), 120.14
(CH), 111.59 (CH), 110.93 (CH), 80.79 (CH2), 79.60 (CH), 55.86 (CH3),
55.83 (CH3), 51.47 (CH3), 51.19 (CH), 49.93 (CH2), 21.54 (CH3).
4.3.8. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-7,8-dimethoxy-2-tosyl-
2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-propenoate (29c). White
needles: mp 99e100  C (n-hexane/AcOEt); IR (KBr) 3506, 1719,
1653 cm
1; EIMS m/z 461 (Mþ), 443, 429, 306; HRMS m/z calcd for
C23H27NO7S: 461.1507, found 461.1535; 1H NMR (400 MHz, CDCl3)
d 7.69 (d, J¼8.3 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H), 7.04 (dd, J¼15.6,
4.6 Hz, 1H), 6.79 (s, 3H), 6.68 (s, 3H), 5.50 (dd, J¼15.6, 2.2 Hz, 1H),
4.60 (dd, J¼14.9, 1.4 Hz, 1H), 4.19e4.10 (m, 1H), 4.00e3.92 (m, 2H),
3.91 (s, 3H), 3.87 (d, J¼14.9 Hz, 1H), 3.86 (s, 3H), 3.67 (s, 3H), 3.09 (d,
J¼13.9 Hz, 1H), 2.54 (d, J¼8.3 Hz, 1H), 2.44 (s, 3H); 13C NMR
(68 MHz, CDCl3) d 166.47 (C), 148.55 (C), 148.11 (C), 146.07 (CH),
143.82 (C), 135.83 (C), 129.94 (CH2), 129.07 (C), 127.45 (C), 127.07
(CH2), 122.94 (CH), 116.11 (CH), 113.41 (CH), 68.99 (CH), 56.08
(CH3), 56.00 (CH3), 54.80 (CH), 53.46 (CH2), 53.20 (CH2), 51.64
(CH3), 21.51 (CH3). Anal. Calcd for C23H27NO7S: C, 59.85; H, 5.90; N,
3.03. Found: C, 59.62; H, 6.05; N, 2.93.
4.3.9. Methyl (2E,4SR)-4-(1,3-benzodioxol-5-yl-methyl)-4-[(5RS)-3-
tosyloxazolidin-5-yl]-2-butenoate (28d). Amorphous: IR (neat)
1734, 1655, 1350 cm
1; EIMS m/z 445 (Mþ), 415, 342, 290; HRMS
m/z calcd for C22H23NO7S: 445.1194, found 445.1218; 1H NMR
(270 MHz, CDCl3) d 7.72 (d, J¼8.2 Hz, 2H), 7.37 (d, J¼8.5 Hz, 2H), 6.95
(dd, J¼15.8, 7.2 Hz, 1H), 6.74 (d, J¼7.2 Hz, 1H), 6.50 (s, 1H), 6.48 (d,
J¼7.2 Hz, 1H), 5.96 (s, 2H), 5.64 (dd, J¼15.8, 1.3 Hz, 1H), 5.06 (d,
J¼6.2 Hz, 1H), 4.83 (d, J¼6.3 Hz, 1H), 3.98 (ddd, J¼8.6, 7.3, 6.6 Hz,
1H), 3.68 (s, 3H), 3.32 (dd, J¼11.5, 6.6 Hz, 1H), 2.98 (dd, J¼11.5,
7.3 Hz, 1H), 2.95 (dd, J¼8.6, 7.3 Hz, 1H), 2.48 (s, 3H); 13C NMR
(68 MHz, CDCl3) d 166.38 (C), 148.17 (C), 147.17 (C), 147.04 (CH),
144.43 (C), 134.02 (C), 130.94 (C), 129.87 (CH2), 127.86 (CH2),
122.46 (CH), 121.30 (CH), 108.76 (CH), 108.05 (CH), 101.22 (CH2),
80.83 (CH2), 79.53 (CH), 51.51 (CH3), 51.25 (CH), 49.96 (CH2), 21.55
(CH3).
4.3.10. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-7,8-methylenedioxy-2-
tosyl-2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-propenoate
(29d). Amorphous; IR (ATR) 3493, 2900, 1718 cm
1; MS (FABþ) m/z
4132 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
446 (MþHþ), 391, 307, 279; HRMS m/z calcd for C22H24NO7S
446.1273, found 446.1298; 1H NMR (400 MHz, CDCl3) d 7.69 (d,
J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 7.03 (dd, J¼15.6, 4.8 Hz, 1H),
6.78 (s, 1H), 6.67 (s, 1H), 5.97 (s, 2H), 5.55 (d, J¼15.6 Hz, 1H), 4.51 (d,
J¼15.1 Hz, 1H), 4.16e4.07 (m, 1H), 3.98e3.82 (m, 3H), 3.68 (s, 3H),
3.11 (d, J¼13.1 Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 166.5 (C), 147.7 (C), 147.1 (C), 146.0 (CH), 143.9 (C), 135.9 (C), 130.3
(C), 130.0 (CH2), 129.2 (C), 127.1 (CH2), 123.0 (CH), 112.9 (CH),
110.6 (CH), 101.5 (CH2), 69.1 (CH), 60.41 (CH2), 54.6 (CH), 53.2 (CH2),
51.7 (CH3), 21.5 (CH3).
4.3.11. Methyl (2E,4SR)-4-(3,4-dimethoxyphenyl)-4-[(6SR)-3-tosyl-
1,3-oxazinan-6-yl]-2-butenoate (33). Amorphous: IR (KBr) 2956,
1723, 1657 cm
1; EIMS m/z 475 (Mþ), 445, 372, 155; HRMS m/z
calcd for C24H29NO7S: 475.1665, found 475.1675; 1H NMR
(270 MHz, CDCl3) d 7.76 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 7.12
(dd, J¼15.8, 7.5 Hz, 1H), 6.77 (d, J¼7.9 Hz, 2H), 6.58 (dd, J¼7.9, 1.9 Hz,
1H), 6.54 (d, J¼1.9 Hz, 1H), 5.70 (dd, J¼15.8, 1.3 Hz, 1H), 5.60 (d,
J¼11.2 Hz, 1H), 4.42 (d, J¼11.2 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H),
3.89e3.78 (m, 1H), 3.72 (s, 3H), 3.64 (dd, J¼13.1, 7.5 Hz, 1H),
3.15e3.04 (m, 1H), 2.45 (s, 3H), 1.09e0.99 (m, 1H); 13C NMR
(100 MHz, C6D6) d 166.55 (C), 150.30 (C), 149.46 (C), 148.53 (CH),
143.30 (C), 138.16 (C), 131.52 (C), 129.71 (CH2), 128.09 (CH2),
122.77 (CH), 120.82 (CH), 112.83 (CH), 112.55 (CH), 79.49 (CH), 78.18
(CH2), 55.72 (CH3), 55.64 (CH3), 53.63 (CH), 51.03 (CH3), 44.15 (CH2),
27.44 (CH2), 21.15 (CH3).
4.3.12. Methyl (2E)-3-[(5SR,6RS)-5-hydroxy-8,9-dimethoxy-2-tosyl-
1, 2 , 3 , 4 , 5 , 6 - h e x a h y d r o - 2 - b e n z a z o c i n - 6 - y l ] - p r o p e n o a t e
(34). Amorphous: IR (KBr) 3504, 1721, 1655 cm
1; EIMS m/z 475
(Mþ), 443, 320; HRMS m/z calcd for C24H29NO7S: 475.1663, found
475.1638; 1H NMR (270 MHz, CDCl3) d 7.70 (d, J¼8.2 Hz, 2H), 7.32 (d,
J¼8.2 Hz, 2H), 7.31 (dd, J¼15.5, 6.5 Hz, 1H), 6.91 (s, 1H), 6.58 (s, 1H),
6.07 (d, J¼15.5 Hz, 1H), 4.68 (d, J¼14.5 Hz, 1H), 4.18 (d, J¼14.5 Hz,
1H), 4.18e3.93 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.63
(dd, J¼14.5, 8.5 Hz, 1H), 3.28 (dd, J¼14.5, 6.5 Hz, 1H), 2.44 (s, 3H),
1.98e1.82 (m, 1H), 1.89 (d, J¼3.3 Hz, 1H), 1.47 (dd, J¼16.1, 7.9 Hz,
1H); 13C NMR (68 MHz, CDCl3) d 166.56 (C), 148.90 (C), 148.18 (C),
147.76 (CH), 143.39 (C), 136.43 (C), 130.51 (CH), 129.83 (CH2),
127.63 (C), 127.02 (CH2), 123.86 (CH), 114.12 (CH), 110.14 (CH),
74.21 (CH), 56.10 (CH3), 55.96 (CH3), 51.74 (CH3), 50.65 (CH2), 47.61
(CH2), 42.78 (CH2), 33.74 (CH2), 21.51 (CH3).
4.3.13. Methyl 3-[(2RS,3SR)-3-hydroxy-1-tosylpyrrolidin-2-yl]-2E-
propenoate (35). Amorphous; IR (KBr) 3512, 1721, 1248 cm
1; EIMS
m/z 325 (Mþ), 307, 294, 170; HRMS m/z calcd for C15H19NO5S:
325.0982, found 325.0964; 1H NMR (270 MHz, CDCl3) d 7.73 (d,
J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 6.86 (dd, J¼15.5, 5.2 Hz, 1H),
6.18 (dd, J¼15.5, 1.6 Hz, 1H), 4.15 (br s, 2H), 3.76 (s, 3H), 3.56 (ddd,
J¼8.2, 2.6, 2.3 Hz, 1H), 3.37 (dt, J¼9.8, 6.9 Hz, 1H), 2.42 (s, 3H),
2.06e1.92 (m, 1H), 1.82e1.74 (m, 1H); 13C NMR (68 MHz, CDCl3)
d 166.48 (C), 144.95 (CH), 143.81 (C), 133.96 (C), 129.65 (CH2),
127.74 (CH2), 122.92 (CH), 75.05 (CH), 68.75 (CH), 51.71 (CH3),
46.36 (CH2), 31.86 (CH2), 21.55 (CH3).
4.3.14. Methyl 3-[(2RS,3SR)-3-hydroxy-1-(3-methoxyphenyl)pyrroli-
din-2-yl]-2E-propenoate (36). Pale yellow oil: IR (neat) 3464,
1725 cm
1; EIMS m/z 277 (Mþ), 259; HRMS m/z calcd for C15H19NO4
277.1314, found 277.1299; 1H NMR (270 MHz, CDCl3) d 7.12 (t,
J¼8.0 Hz, 1H), 6.95 (dd, J¼15.5, 4.6 Hz, 1H), 6.30 (dd, J¼8.0, 2.0 Hz,
1H), 6.16 (dd, J¼8.0, 2.0 Hz, 1H), 6.09 (t, J¼2.0 Hz, 1H), 5.92 (dd,
J¼15.5, 1.6 Hz, 1H), 4.30 (br d, J¼3.0 Hz, 1H), 4.18 (br d, J¼4.0 Hz, 1H),
3.77 (s, 3H), 3.70 (s, 3H), 3.58e3.51 (m, 2H), 2.21e1.91 (m, 3H); 13C
NMR (68 MHz, CDCl3) d 166.7 (C), 160.7 (C), 148.2 (C), 146.0 (CH),
129.9 (CH), 122.2 (CH), 105.6 (CH), 101.6 (CH), 98.9 (CH), 75.5 (CH),
69.1 (CH), 55.1 (CH3), 51.6 (CH3), 46.2 (CH2), 31.5 (CH2).
4.3.15. Methyl 3-[(2RS,3SR)-1-(3-methoxyphenyl)-3-tosyloxypyr-
rolidin-2-yl]-2E-propenoate (37). Pale yellow oil: IR (neat)
1721 cm
1; EIMS m/z (Mþ) 431, 354; HRMS m/z calcd for
C22H25NO6S 431.1401, found 431.1403; 1H NMR (400 MHz, CDCl3)
d 7.77 (d, J¼8.1 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H), 7.09 (t, J¼8.1 Hz, 1H),
6.81 (dd, J¼15.4, 4.0 Hz, 1H), 6.31 (dd, J¼8.1, 1.5 Hz, 1H), 6.06 (dd,
J¼8.1, 1.5 Hz, 1H), 5.97 (br, 1H), 5.87 (dd, J¼15.4, 1.5 Hz, 1H), 4.88 (br,
1H), 4.34e4.25 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.62e3.40 (m, 2H),
2.45 (s, 3H), 2.25e2.08 (m, 2H); 13C NMR (68 MHz, CDCl3) d 166.2
(C), 160.6 (C), 147.5 (C), 145.2 (C), 144.0 (CH), 133.7 (C), 130.1 (CH2),
129.9 (CH), 127.7 (CH2), 123.5 (CH), 105.5 (CH), 102.1 (CH), 99.0
(CH), 83.8 (CH), 66.4 (CH), 55.1 (CH3), 51.7 (CH3), 46.3 (CH2), 29.6
(CH2), 21.7 (CH3).
4.3.16. Methyl 3-[(2RS,3SR)-3-hydroxy-1-(5-methoxy-2-tosylphenyl)
pyrrolidin-2-yl]-2E-propenoate (38). Colorless oil: IR (neat) 3486,
1725 cm
1; EIMS m/z 431 (Mþ), 372; HRMS (EI) m/z calcd for
C22H25NO6S 431.1403, found 431.1414; 1H NMR (270 MHz, C6D6)
d 8.39 (d, J¼8.9 Hz, 1H), 7.82 (d, J¼8.2 Hz, 2H), 6.90 (d, J¼7.9 Hz, 2H),
6.48 (d, J¼2.3 Hz, 1H), 6.21 (dd, J¼8.9, 2.3 Hz, 1H), 5.68 (d,
J¼15.5 Hz, 1H), 5.44 (dd, J¼15.8, 8.2 Hz, 1H), 4.07 (dt, J¼8.9, 4.0 Hz,
1H), 3.65e3.52 (m, 1H), 3.45e3.34 (m, 1H), 3.16 (s, 3H), 3.04 (s, 3H),
2.59 (dt, J¼8.9, 8.2 Hz, 1H), 2.11 (s, 3H), 2.17e1.98 (m, 1H), 1.51e1.25
(m, 1H); 13C NMR (100 MHz, C6D6) d 165.4 (C), 164.5 (C), 149.9 (C),
146.2 (CH), 143.4 (C), 140.6 (C), 133.0 (CH), 131.2 (C), 129.2 (CH2),
128.5 (CH2), 124.1 (CH), 110.7 (CH), 109.0 (CH), 75.7 (CH), 71.1
(CH), 54.9 (CH3), 50.7 (CH3), 33.0 (CH2), 30.0 (CH2), 21.6 (CH3).
4.3.17. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-7,8-dimethoxy-1-tosyl-
2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-propenoate
(39b). Colorless oil: IR (neat) 3518, 1723 cm
1; EIMS m/z 461
(Mþ) 443, 429, 306, 288, 274; HRMS m/z calcd for C23H27NO7S
461.1507, found 461.1489; 1H NMR (270 MHz, DMSO-d6, 100  C)
d 7.68 (d, J¼8.2 Hz, 2H), 7.42 (d, J¼8.2 Hz, 2H), 7.07 (dd, J¼15.8,
7.9 Hz, 1H), 6.71 (s, 1H), 6.64 (s, 1H), 5.57 (1H, dd, J¼15.8, 1.3 Hz),
4.58 (1H, d, J¼4.3 Hz), 3.78 (1H, dd, J¼7.9, 3.6 Hz), 3.74 (s, 3H),
3.68 (s, 3H), 3.67e3.60 (m, 2H), 3.65 (s, 3H), 3.26 (t, J¼7.9 Hz, 1H),
2.42 (s, 3H), 1.79e1.68 (m, 2H); 13C NMR (270 MHz, DMSO-d6,
100  C) d 165.33 (C), 147.69 (C), 147.40 (C), 147.04 (CH), 142.81 (C),
137.55 (C), 130.34 (C), 129.60 (C), 129.22 (CH2), 126.31 (CH2),
121.92 (CH), 113.68 (CH), 112.89 (CH), 67.40 (CH), 55.75 (CH3),
55.50 (CH3), 51.15 (CH), 50.44 (CH3), 43.61 (CH2), 33.12 (CH2),
20.24 (CH3).
4.3.18. Methyl (2E)-3-[(4SR,5RS)-4-hydroxy-6,8-dimethoxy-1-tosyl-
2,3,4,5-tetrahydro-1H-2-benzazepin-5-yl]-propenoate
(39c). Colorless oil: IR (neat) 3510, 1715 cm
1, EIMS m/z 461
(Mþ), 429, 306, 288; HRMS m/z calcd for C23H27NO7S 461.1507,
found 461.1486; 1H NMR (270 MHz, CDCl3, 50  C) d 7.82 (d,
J¼8.0 Hz, 2H), 7.32 (d, J¼8.0 Hz, 2H), 7.19 (dd, J¼15.5, 6.6 Hz, 1H),
6.40e6.35 (m, 2H), 5.72 (dd, J¼15.5, 1.6 Hz, 1H), 4.46 (br, 1H), 4.20
(br, 1H), 3.94 (dt, J¼14.0, 4.3 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H),
3.67 (s, 3H), 3.32 (ddd, J¼13.5, 11.2, 2.0 Hz, 1H), 2.43 (s, 3H), 2.11
(br t, J¼13.5 Hz, 1H), 1.86e1.72 (br d, J¼14.5 Hz, 1H), 1.56 (br, 1H);
13
C NMR (270 MHz, CDCl3) d 166.9 (C), 159.8 (C), 159.5 (C), 146.8
(CH), 143.6 (C), 142.1 (C), 138.7 (C), 129.8 (CH2), 127.5 (CH2),
122.5 (CH), 115.8 (C), 103.5 (CH), 97.9 (CH), 68.6 (CH), 56.0 (CH3),
55.3 (CH3), 51.5 (CH3), 44.6 (CH2), 44.2 (CH), 33.8 (CH2), 21.5
(CH3).
4.4. Synthesis of 5,11-methanomorphanthridine
4.4.1. Ethyl (4S,2E)-4-[N-(3,4-dimethoxybenzyl)-4-methylpheny-
lsulfonamido]-5-hydroxy-2-pentenoate (41). To a solution of 40
(23.4 g, 0.167 mol) in CH3CN (400 mL) were added 9c (52.4 g,
0.163 mol), Pd(PPh3)4 (3.82 g, 3.28 mmol, 0.02 equiv), and Et3N
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
(24.0 mL, 0.164 mol) at 0  C. The reaction mixture was stirred for
1 h and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with n-
hexane/AcOEt (2:1) to give 41 (65.7 g, 0.142 mol, 87%) as white
crystals: mp 92e93  C (n-hexane/AcOEt); [a]20 D 21.5 (c 1.04, CHCl3);
IR (CHCl3) 3622, 1717, 1599, 1518 cm
1; EIMS m/z 463 (Mþ), 417, 308,
290; HRMS m/z calcd for C23H29NO7S 463.1665, found 463.1666; 1H
NMR (400 MHz, CDCl3) d 7.73 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz,
2H), 6.90 (d, J¼1.6 Hz, 1H), 6.84 (dd, J¼8.2, 1.6 Hz, 1H), 6.79 (d,
J¼8.2 Hz, 1H), 6.57 (dd, J¼16.0, 6.6 Hz, 1H), 5.67 (dd, J¼16.0, 1.3 Hz,
1H), 4.59 (d, J¼15.5 Hz, 1H), 4.54 (dd, J¼13.2, 6.6 Hz, 1H), 4.15 (q,
J¼7.1 Hz, 1H), 4.13 (d, J¼15.5 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H),
3.64e3.51 (m, 2H), 2.43 (s, 3H), 1.70 (br s, 1H), 1.26 (t, J¼7.1 Hz, 3H);
13
C NMR (100 MHz, CDCl3) d 165.19 (C), 148.99 (C), 148.52 (C),
143.46 (C), 141.63 (CH), 137.18 (C), 129.52 (CH2), 129.12 (C), 126.99
(CH2), 124.51 (CH), 120.28 (CH), 110.96 (CH), 110.77 (CH), 62.31
(CH2), 60.37 (CH2), 60.12 (CH), 55.61 (CH3), 55.50 (CH3), 48.79
(CH2), 21.20 (CH3), 13.87 (CH3). Anal. Calcd for C23H29NO7S: C,
59.59; H, 6.31; N, 3.02. Found: C, 59.55; H, 6.36; N, 2.93.
Absolute configuration of 41 was determined as following.
Compound 41 was converted to (S)-D by silylation. On the other
hand, (R)-D was synthesized from L-serine derivative A by four
steps. Signs of optical rotation for them were confirmed to be
reverse.
MeO
Br
MeO
TBDPSO Na2CO3 MeO
TsHN COOMe acetone MeO
reflux
A B
49%
OTBDPS
1) TEMPO, PhI(OAc)2 MeO COOMe
2) Wittig react. MeO NTs
89% (R)-D
o
[α]D (CHCl3) = -4.4
4.4.1.1. Compound B. To a solution of A18 (104.2 mg,
0.204 mmol) in acetone (4 mL) were added Na2CO3 (174.6 mg,
1.65 mmol, 8 equiv) and 3,4-dimethoxybenzyl bromide (133.2 mg,
0.576 mmol, 3 equiv). The reaction mixture was refluxed for 48 h,
then quenched with H2O, and extracted with CH2Cl2. The extract
was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel eluted with n-hexane/AcOEt (4:1) to give B
(66.3 mg, 0.100 mmol, 49%) as a colorless viscous oil: [a]20 D
20.7 (c
0.611, CHCl3); IR (ATR) 2933, 1741, 1515 cm
1; MS (FABþ) m/z 662
(MþHþ), 604, 506, 448; HRMS m/z calcd for C36H44NO7SSi
662.2608; found 662.2596; 1H NMR (600 MHz, CDCl3) d 7.72 (d,
J¼8.2 Hz, 2H), 7.51 (d, J¼6.9 Hz, 2H), 7.46e7.38 (m, 4H), 7.35 (t,
J¼7.6 Hz, 2H), 7.31 (t, J¼7.6 Hz, 2H), 7.24 (d, J¼8.2 Hz, 2H), 6.79 (s,
1H), 6.75 (d, J¼8.2 Hz, 1H), 6.66 (d, J¼8.2 Hz, 1H), 4.69 (dd, J¼6.9,
5.5 Hz, 1H), 4.61 (d, J¼15.8 Hz, 1H), 4.49 (d, J¼15.8 Hz, 1H), 3.97 (dd,
J¼11.0, 5.5 Hz, 1H), 3.88 (dd, J¼11.0, 6.9 Hz, 1H), 3.83 (s, 3H), 3.70 (s,
3H), 3.47 (s, 3H), 2.41 (s, 3H), 0.97 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 169.58 (C), 148.75 (C), 148.28 (C), 143.29 (C), 137.16 (C),
135.54 (CH2), 135.44 (CH2), 132.61 (C), 132.53 (C), 129.80 (CH),
129.72 (CH), 129.52 (C), 129.36 (CH2), 127.66 (CH2), 127.61
(CH2), 127.55 (CH2), 120.25 (CH), 110.96 (CH), 110.59 (CH), 63.07
4133
(CH2), 60.88 (CH), 55.81 (CH3), 55.56 (CH3), 51.85 (CH3), 49.98
(CH2), 26.63 (CH33), 21.48 (CH2), 19.01 (C).
4.4.1.2. Compound C. To a solution of ester B (21.0 mg,
31.7 mmol) in THF (0.04 mL) and EtOH (0.36 mL) were added LiCl
(9.2 mg, 0.217 mmol, 6.8 equiv) and NaBH4 (6.3 mg, 0.167 mmol,
5.3 equiv) at 0  C. The reaction mixture was stirred for 6 h. Then it
was quenched with satd citric acid aqueous and extracted with
CH2Cl2. The extract was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(2:1) to give C (20.1 mg, 31.7 mmol, quant) as a colorless oil: [a]20 D
9.29 (c 0.680, CHCl3); IR (ATR) 3528, 2931, 1594; MS (FABþ) m/z 662
(MþHþ), 604, 506, 448; HRMS m/z calcd for C35H44NO6SSi
634.2659; found 634.2650; 1H NMR (600 MHz, CDCl3) d 7.71 (d,
J¼8.3 Hz, 2H), 7.51 (d, J¼7.5 Hz, 2H), 7.48 (d, J¼7.5 Hz, 2H), 7.47e7.40
(m, 2H), 7.36 (t, J¼7.5 Hz, 2H), 7.35 (t, J¼7.5 Hz, 2H), 7.21 (d,
J¼8.3 Hz, 2H), 6.85 (s, 1H), 6.69 (d, J¼7.5 Hz, 1H), 6.67 (d, J¼7.5 Hz,
1H), 4.46 (d, J¼15.8 Hz, 1H), 4.39 (d, J¼15.8 Hz, 1H), 4.03 (quint,
J¼6.2 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.63e3.51 (m, 4H), 2.38 (s,
3H), 0.96 (s, 9H); 13C NMR (100 MHz, CDCl3) d 149.17 (C), 148.60 (C),
143.27 (C), 137.92 (C), 135.50 (CH2), 135.42 (CH2), 132.67 (C),
130.27 (C), 129.94 (CH), 129.87 (CH), 129.74 (CH2), 127.81 (CH2),
127.76 (CH2), 127.15 (CH2), 120.17 (CH), 110.95 (CH), 110.82 (CH),
OTBDPS OTBDPS
NaBH4, LiCl MeO
COOMe
NTs THF, EtOH MeO NTs OH
H2O
C
quant.
TBDPSCl
OTBDPS imidazole
MeO COOMe THF
41
MeO NTs
(S)-D
[α ]D (CHCl3) = +5.9o
62.88 (CH2), 62.26 (CH2), 61.41 (CH), 55.86 (CH3), 55.77 (CH3), 48.98
(CH2), 26.76 (CH33), 21.51 (CH2), 19.03 (C).
4.4.1.3. Compound (R)-D. To a solution of alcohol C (26.9 mg,
42.4 mmol) in CH2Cl2 (3 mL) were added TEMPO (3.1 mg, 9.6 mmol,
0.2 equiv) and PhI(OAc)2 (109.5 mg, 0.701 mmol, 17 equiv) at room
temperature. The reaction mixture was stirred for 3 h. Then it was
quenched with saturated Na2S2O3 aqueous and extracted with
CH2Cl2. The extract was washed with saturated NaHCO3 and brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was used directly in the next step without further purifi-
cation. To a suspension of NaH (60% purity, 5.5 mg, 0.138 mmol,
3 equiv) in THF (2 mL) at
30  C was added (EtO)2P(O)CH2CO2Et
(30.1 mL, 0.150 mmol, 3.5 equiv). After being stirred for 2 h, a solu-
tion of the residue in THF (1 mL) was added dropwise to the re-
action mixture. The reaction mixture was further stirred for 16 h
and quenched with H2O and extracted with CH2Cl2. The extract was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel eluted with n-hexane/AcOEt (4:1) to give (R)-
D (26.4 mg, 37.7 mmol, 89%, two steps) as a colorless oil: [a]20
D
4.40
(c 0.305, CHCl3); IR (ATR) 2932, 1720, 1516; MS (FABþ) m/z 702
4134 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
(MþHþ), 644, 564, 474; HRMS m/z calcd for C39H48NO7SSi
702.2921; found 702.2894; 1H NMR (400 MHz, CDCl3) d 7.67 (d,
J¼8.3 Hz, 2H), 7.53e7.39 (m, 6H), 7.38e7.31 (m, 4H), 7.23 (d,
J¼8.3 Hz, 2H), 6.71 (d, J¼1.7 Hz, 1H), 6.68e6.58 (m, 3H), 5.67 (dd,
J¼15.9, 1.5 Hz, 1H), 4.62e4.53 (m, 1H), 4.44 (d, J¼15.4 Hz, 1H), 4.18
(d, J¼15.4 Hz, 1H), 4.14 (q, J¼7.1 Hz, 2H), 3.83 (s, 3H), 3.71 (dd,
J¼10.5, 6.6 Hz, 1H), 3.68 (s, 3H), 3.54 (dd, J¼10.5, 7.6 Hz, 1H), 2.40 (s,
3H), 1.25 (t, J¼7.1 Hz, 3H), 0.96 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 165.56 (C), 148.98 (C), 148.53 (C), 143.32 (C), 142.91 (CH), 137.75
(C), 135.49 (CH2), 135.45 (CH2), 132.77 (C), 132.68 (C), 129.83
(CH), 129.80 (CH), 129.66 (CH2), 129.38 (C), 127.72 (CH2), 127.69
(CH2), 127.18 (CH2), 124.51 (CH), 120.49 (CH), 111.07 (CH), 110.61
(CH), 64.27 (CH2), 60.44 (CH2), 60.07 (CH), 55.79 (CH3), 55.60 (CH3),
49.19 (CH2), 26.70 (CH33), 21.47 (CH2), 19.03 (C), 14.15 (CH3).
4.4.1.4. Compound (S)-D. To a solution of 41 (22.8 mg, 49.2 mmol)
in THF (1 mL) were added imidazole (8.5 mg, 0.124 mmol,
2.5 equiv) and TBDPSCl (25.6 mL, 98.4 mmol, 2 equiv). The mixture
was stirred at room temperature for 2 h, then quenched with H2O,
and extracted with Et2O. The extract was washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel eluted with n-
hexane/AcOEt (4:1) to give (S)-D (32.2 mg, 45.9 mmol, 93%) as
a colorless oil: [a]20 1
D 5.86 (c 1.07, CHCl3); H and
13
C NMR of (S)-D
were identical with those of (R)-D.
4.4.2. (S)-N-{5-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)pentan-2-
yl}-N-(3,4-dimethoxybenzyl)-4-methylbenzenesulfonamide (42). A
mixture of 41 (21.2 g, 45.7 mmol), 20% Pd(OH)2eC (5.5 g) in EtOH
(400 mL) was stirred under H2 atmosphere at room temperature for
5 h. The reaction mixture was filtered, and the filtrate was con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(1:1) to give reductive compound (20.4 g, 44.8 mmol, 98%) as white
crystals. To a solution of this compound (19.0 g, 41.0 mmol) in THF
(200 mL) were added imidazole (5.60 g, 82.0 mmol, 2 equiv) and
TBDPSCl (12.8 mL, 49.2 mmol, 1.2 equiv) at 0  C. The mixture was
stirred at room temperature for 24 h, then quenched with H2O, and
extracted with Et2O. The extract was dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(2:1) to give silyl ether (24.4 g, 34.9 mmol, 85%) as a pale yellow oil.
To a solution of silyl ether (49.5 g, 70.5 mmol) in THF (300 mL) was
added LiAlH4 (2.69 g, 70.5 mmol) at 0  C. The mixture was stirred at
room temperature for 3 h, then quenched with a small amount of
H2O. The precipitate was removed by filtration. The filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(1:1) to give alcohol (45.4 g, 70.5 mmol) as a pale yellow oil. To this
alcohol (45.4 g, 70.5 mmol) in THF (300 mL) were added NaH (60%
purity, 53.7 g, 1.43 mol, 20 equiv), BnBr (50 mL, 430 mmol, 6 equiv),
and KI (70.0 g, 422 mmol, 6 equiv) at 0  C. The mixture was stirred at
60  C for 6 h, then quenched with H2O, and extracted with Et2O. The
extract was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with n-hexane/AcOEt (4:1) to give 42 (51.2 g,
68.4 mmol, 97%) as a pale yellow oil: [a]20 D
17.6 (c 1.01, CHCl3); IR
(ATR) 2931, 1594, 1514 cm
1; EIMS m/z 751 (Mþ), 694, 596; HRMS
m/z calcd for C44H53NO6SSi: 751.3363, found 751.3341; 1H NMR
(400 MHz, CDCl3) d 7.66 (d, J¼8.3 Hz, 2H), 7.52 (dd, J¼8.1, 1.4 Hz, 2H),
7.49 (dd, J¼7.8, 1.4 Hz, 2H), 7.46e7.23 (m, 11H), 7.16 (d, J¼8.1 Hz, 2H),
6.82 (d, J¼1.7 Hz, 1H), 6.68 (dd, J¼8.1, 1.7 Hz, 1H), 6.63 (d, J¼8.1 Hz,
1H), 4.41 (d, J¼15.6 Hz, 1H), 4.39 (s, 2H), 4.27 (d, J¼15.6 Hz, 1H),
3.97e3.84 (m, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.56 (dd, J¼10.5, 6.1 Hz,
1H), 3.36 (dd, J¼10.5, 6.8 Hz, 1H), 3.31e3.18 (m, 1H), 2.36 (s, 3H),
1.72e1.59 (m, 1H), 1.52e1.29 (m, 1H), 0.98 (s, 9H); 13C NMR
(68 MHz, CDCl3) d 148.96 (C), 148.44 (C), 142.79 (C), 138.62 (C),
138.58 (C), 135.55 (CH2), 135.50 (CH2), 133.17 (C), 133.12 (C),
130.57 (C), 129.72 (CH), 129.66 (CH), 129.50 (CH2), 128.29 (CH2),
127.67 (CH2), 127.63 (CH2), 127.45 (CH2), 127.41 (CH), 127.17
(CH2), 120.55 (CH), 111.45 (CH), 110.68 (CH), 72.70 (CH2), 69.79
(CH2), 65.47 (CH2), 60.12 (CH), 55.85 (CH3), 55.67 (CH3), 48.32 (CH2),
26.81 (CH33), 26.79 (CH2), 26.70 (CH2), 21.42 (CH3), 19.10 (C).
4.4.3. N-[(4S,2E)-7-(Benzyloxy)-1-hydroxy-2-hepten-4-yl]-N-(3,4-
dimethoxybenzyl)-4-methylbenzenesulfonamide (43). To a solution
of benzyl ether 42 (51.2 g, 68.1 mmol) in THF (300 mL) was added
TBAF (1.0 M in THF, 82.0 mL, 82.0 mmol, 1.2 equiv) at room tem-
perature. The mixture was stirred for 3 h, then quenched with
H2O, and extracted with CHCl3. The extract was dried over MgSO4
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel eluted with n-hex-
ane/AcOEt (2:1) to give alcohol (32.1 g, 62.7 mmol, 92%) as a pale
yellow oil. According to the conversion of 14 into 16, 43 was ob-
tained in 77% yield from this alcohol as a pale yellow oil: [a]20 D

14.6 (c 1.07, CHCl3); IR (ATR) 3530, 2936, 1594, 1154 cm
1; EIMS
m/z 539 (Mþ), 384, 320; HRMS m/z calcd for C30H37NO6S 539.2342,
found 539.2362; 1H NMR (400 MHz, CDCl3) d 7.68 (d, J¼8.3 Hz,
2H), 7.36e7.23 (m, 7H), 6.92 (d, J¼1.7 Hz, 1H), 6.79 (dd, J¼8.3,
1.7 Hz, 1H), 6.73 (d, J¼8.3 Hz, 1H), 5.54 (dt, J¼16.6, 5.3 Hz, 1H), 5.42
(dd, J¼16.6, 6.8 Hz, 1H), 4.40 (d, J¼15.3 Hz, 1H), 4.39 (s, 2H), 4.30
(q, J¼6.8 Hz, 1H), 4.17 (d, J¼15.3 Hz, 1H), 3.95 (t, J¼5.1 Hz, 1H), 3.86
(s, 3H), 3.80 (s, 3H), 3.35e3.27 (m, 1H), 3.26e3.18 (m, 1H), 2.40 (s,
3H), 1.65e1.40 (m, 4H), 1.15e1.07 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 148.99 (C), 148.49 (C), 143.13 (C), 138.54 (C), 138.32 (C),
132.67 (CH), 130.37 (C), 129.53 (CH2), 129.14 (CH), 128.34
(CH2), 127.53 (CH2), 127.50 (CH), 127.30 (CH2), 120.58 (CH),
111.62 (CH), 110.59 (CH), 72.76 (CH2), 69.63 (CH2), 62.82 (CH2),
59.54 (CH), 55.91 (CH3), 55.82 (CH3), 48.13 (CH2), 29.59 (CH2),
26.64 (CH2), 21.48 (CH3).
4.4.4. Methyl (2E,4S,5S,6S)-9-(benzyloxy)-6-[N-(3,4-
dimethoxybenzyl)-4-methylphenylsulfonamido]-4,5-epoxy-2-
nonnenate (44). To a solution of L-(þ)-DIPT (4.57 g, 19.5 mmol) and
Ti(OiPr)4 (4.6 mL, 15.6 mmol) in CH2Cl2 (30 mL) was added a solution
of 43 (7.02 g, 13.0 mmol) in CH2Cl2 (50 mL) at
30  C under an argon
atmosphere. After being stirred for 30 min, TBHP (4.9 M in CH2Cl2,
38 mL, 186 mmol) was added dropwise to the mixture at
30  C.
After being further stirred for 15 h, the reaction mixture was
quenched with Me2S (16 mL, 223 mmol). After 2 h, the reaction
mixture was filtered through a Celite pad and then the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(1:1) to give epoxy alcohol (5.67 g, 10.1 mmol, 78%) as a pale yellow
oil. According to the conversion of 14 into 15, 44 was obtained in 90%
yield from this epoxy alcohol as a pale yellow oil: [a]20D
0.77 (c 1.04,
CHCl3); IR (neat) 2954, 1725, 1518, 816 cm
1; EIMS m/z 609 (Mþ),
454, 321, 248; HRMS m/z calcd for C33H39NO8S 609.2396; found
609.2385; 1H NMR (400 MHz, CDCl3) d 7.69 (d, J¼8.3 Hz, 2H),
7.37e7.25 (m, 7H), 6.86 (d, J¼1.9 Hz, 1H), 6.80 (dd, J¼8.2, 1.9 Hz, 1H),
6.72 (d, J¼8.2 Hz, 1H), 6.30 (dd, J¼15.6, 7.3 Hz, 1H), 5.96 (d, J¼15.6 Hz,
1H), 4.54 (d, J¼15.6 Hz, 1H), 4.43 (d, J¼12.2 Hz, 1H), 4.40 (d,
J¼12.2 Hz, 1H), 4.14 (d, J¼15.6 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.74
(s, 3H), 3.41 (dd, J¼15.2, 7.2 Hz, 1H), 3.30 (td, J¼5.8, 1.9 Hz, 1H), 3.17
(dd, J¼7.2, 1.9 Hz, 1H), 2.45 (dd, J¼7.2, 1.9 Hz, 1H), 2.40 (s, 3H),
1.76e1.59 (m, 2H), 1.48e1.28 (m, 2H); 13C NMR (68 MHz, CDCl3)
d 165.78 (C), 149.28 (C), 148.93 (C), 143.76 (CH), 143.55 (C), 138.44 (C),
137.96 (C), 129.81 (CH2), 129.72 (C), 128.38 (CH2), 127.59 (CH),
127.52 (CH2), 127.07 (CH2), 123.81 (CH), 121.05 (CH), 111.44 (CH),
110.92 (CH), 72.82 (CH2), 69.38 (CH2), 62.49 (CH), 60.27 (CH), 55.88
(CH3), 55.74 (CH3), 55.51 (CH), 51.72 (CH3), 48.54 (CH2), 26.83 (CH2),
26.10 (CH2), 21.49 (CH3).
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
4.4.5. Methyl (2E)-3-{(3S,4R,5S)-3-[3-(benzyloxy)propyl]-4-
hydroxy-7,8-dimethoxy-2-tosyl-2,3,4,5-tetrahydro-1H-2-benzazepin-
5-yl}acrylate (45). To a solution of 44 (5.52 g, 9.05 mmol) in CH2Cl2
(500 mL) was added TMSOTf (0.82 mL, 4.53 mmol, 0.5 equiv) at

30  C under an argon atmosphere. After being stirred for 2 h at

30  C and for 5 h at room temperature, the mixture was quenched
with saturated aqueous NaHCO3 and extracted with CH2Cl2. The
extract was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with n-hexane/AcOEt (2:1) to give 45 (4.81 g,
7.87 mmol, 87%) as a white powder: mp 124  C (n-hexane/AcOEt);

1
[a]20
D 60.4 (c 1.03, CHCl3); IR (ATR) 3483, 1714, 1643 cm ; EIMS m/z
609 (Mþ), 454, 422, 378; HRMS (EI) m/z calcd for C33H39NO8S
609.2396; found 609.2394; 1H NMR (400 MHz, CDCl3) d 7.63 (d,
J¼8.2 Hz, 2H), 7.39e7.27 (m, 5H), 7.19 (dd, J¼15.6, 4.9 Hz, 1H), 7.17
(d, J¼8.2 Hz, 2H), 6.76 (s, 1H), 6.58 (s, 1H), 5.36 (dd, J¼15.6, 2.4 Hz,
1H), 4.50 (d, J¼16.2 Hz, 1H), 4.44 (d, J¼12.4 Hz, 1H), 4.42 (d,
J¼12.4 Hz, 1H), 4.25 (d, J¼16.2 Hz, 1H), 4.14e4.03 (m, 2H).
3.91e3.85 (m, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.66 (s, 3H), 3.32 (t,
J¼6.0 Hz, 2H), 2.58 (d, J¼6.0 Hz, 1H), 2.35 (s, 3H), 1.71e1.54 (m, 2H),
1.54e1.41 (m, 1H), 1.41e1.29 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 166.39 (C), 148.32 (C), 147.96 (C), 146.97 (CH), 143.55 (C), 138.37
(C), 137.30 (C), 130.00 (C), 129.45 (CH2), 128.35 (CH2), 127.52
(CH), 127.47 (CH2), 127.44 (CH2), 126.98 (C), 121.40 (CH), 115.62
(CH), 113.05 (CH), 72.77 (CH2), 72.52 (CH), 69.14 (CH2), 63.19 (CH),
56.00 (CH3), 55.96 (CH3), 54.92 (CH), 51.58 (CH3), 45.99 (CH2), 26.64
(CH2), 26.53 (CH2), 21.53 (CH3).
In order to confirm stereochemistry, 45 was converted to lac-
tone E and H through the following sequences. In 1H NMR spectra
of them, coupling constants for ring juncture were more than 10 Hz.
MeOOC
Pd(OH)2-C
OH OBn H2
MeO MeO
AcOEt
MeO NTs MeO
quant.
45
DIBAH quant.
HOH2C TBDPSO
TBDPSCl
OH OBn
MeO Et3N MeO
MeO NTs CH2Cl2 MeO
F 87%
4.4.5.1. Compound E. A mixture of 45 (43.7 mg, 71.7 mmol) and 20%
Pd(OH)2eC (trace) in AcOEt (2 mL) was stirred under H2 atmo-
sphere at room temperature for 1 h. The reaction mixture was fil-
tered and the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
eluted with n-hexane/AcOEt (1:2) to give E (27.3 mg, 55.9 mmol,
78%) as a colorless amorphous: [a]20 D 26.7 (c 1.26, CHCl3); IR (ATR)
2936, 1730, 1332; MS (FABþ) m/z 490 (MþHþ), 472, 419, 391; HRMS
m/z calcd for C25H32NO7S 490.1894; found 490.1886; 1H NMR
(600 MHz, CDCl3) d 7.78 (d, J¼8.3 Hz, 2H), 7.28 (d, J¼8.3 Hz, 2H),
6.71 (s, 1H), 6.58 (s, 1H), 4.89 (d, J¼15.2 Hz, 1H), 4.44 (d, J¼15.2 Hz,
1H), 4.43e4.39 (m, 1H), 3.93 (dd, J¼11.0, 2.1 Hz, 1H), 3.86 (s, 3H),
3.85 (s, 3H), 3.56 (t, J¼6.2 Hz, 2H), 2.73e2.61 (m, 2H), 2.41 (s, 3H),
4135
2.12e2.01 (m, 3H), 1.60e1.54 (m, 2H), 1.41e1.34 (m, 1H), 1.06e0.98
(m, 1H); 13C NMR (150 MHz, CDCl3) d 169.48 (C), 148.74 (C), 148.46
(C), 143.44 (C), 137.11 (C), 129.62 (CH2), 127.71 (C), 127.54 (CH2),
126.19 (C), 111.38 (CH), 108.80 (CH), 87.59 (CH), 62.01 (CH), 61.90
(CH2), 56.08 (CH32), 48.71 (CH2), 37.49 (CH), 30.21 (CH2), 30.04
(CH2), 29.47 (CH2), 23.48 (CH2), 21.53 (CH3).
4.4.5.2. Compound F. To a solution of 45 (19.6 mg, 32.1 mmol) in
CH2Cl2 (0.5 mL) was added dropwise DIBAH (1.01 M in toluene,
129 mL, 129 mmol, 4 equiv) at
78  C under an argon atmosphere.
This solution was stirred for 40 min, and then quenched with small
amount of H2O. The precipitate was removed by filtration. The fil-
trate was dried over MgSO4 and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel eluted with n-hexane/AcOEt (1:2) to give F (18.7 mg, 32.1 mmol,
quant) as an amorphous: [a]20 D 68.7 (c 0.955, CHCl3); IR (ATR) 3490,
2933, 1607; MS (FABþ) m/z 582 (MþHþ), 564, 460, 426; HRMS m/z
calcd for C32H40NO7S 582.2525; found 582.2519; 1H NMR (600 MHz,
CDCl3) d 7.62 (d, J¼8.2 Hz, 2H), 7.37e7.33 (m, 2H), 7.32e7.27 (m, 3H),
7.17 (d, J¼8.2 Hz, 2H), 6.73 (s, 1H), 6.61 (s, 1H), 5.93 (dd, J¼15.8,
5.5 Hz, 1H), 5.32e5.23 (br, 1H), 4.54 (d, J¼15.8 Hz, 1H), 4.45 (s, 2H),
4.41 (d, J¼15.8 Hz, 1H), 4.14e4.08 (br, 1H), 4.03e3.95 (br, 3H), 3.88 (s,
3H), 3.83 (s, 3H), 3.79e3.71 (br, 1H), 3.47e3.41 (m, 1H), 3.32e3.25
(m, 1H), 2.35 (s, 3H), 2.31e2.22 (m, 1H), 1.90e1.88 (br, 1H), 1.58e1.45
(br, 2H); 13C NMR (150 MHz, CDCl3) d 148.21 (C), 147.65 (C), 143.39
(C), 138.03 (C), 137.71 (C), 130.52 (CH), 129.89 (C), 129.75 (CH), 129.47
(CH2), 128.68 (C), 128.44 (CH2), 127.82 (CH2), 127.78 (CH),
127.34 (CH2), 115.80 (CH), 112.86 (CH), 73.01 (CH2), 72.09 (CH),
69.58 (CH2), 63.61 (CH), 62.76 (CH2), 56.04 (CH3), 55.95 (CH3), 55.08
(CH), 46.29 (CH2), 27.38 (CH2), 26.66 (CH2), 21.49 (CH3).
11 Hz
O
O OH
H
H
NTs
E
10 Hz
TBDPSO
1) Pd(OH)2-C O
OH OBn H O
H2, THF MeO
NTs 2) TEMPO MeO N H
PhI(OAc)2 Ts
G H
32%
4.4.5.3. Compound G. To a solution of F (18.7 mg, 32.1 mmol) in
CH2Cl2 (0.5 mL) were added Et3N (6.7 mL, 38.4 mmol), DMAP (1.4 mg,
11.1 mmol), and TBDPSCl (10 mL, 38.4 mmol) at room temperature.
The mixture was stirred for 1 h, then quenched with H2O, and
extracted with CH2Cl2. The extract was dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(2:1) to give G (22.8 mg, 27.8 mmol, 87%) as a colorless amorphous:
[a]20
D 45.9 (c 1.14, CHCl3); IR (ATR) 3506, 2932, 1607; MS (FABþ) m/z
820 (MþHþ), 802, 762, 646; HRMS m/z calcd for C48H58NO7SSi
820.3703; found 820.3724; 1H NMR (600 MHz, CDCl3) d 7.62e7.57
(m, 6H), 7.39 (t, J¼7.5 Hz, 2H), 7.36e7.29 (m, 6H), 7.28e7.24 (m, 3H),
7.13 (d, J¼8.3 Hz, 2H), 6.70 (s, 1H), 6.58 (s, 1H), 5.93 (dd, J¼15.1,
4136 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
5.5 Hz, 1H), 5.23e5.09 (br, 1H), 4.52 (d, J¼15.8 Hz, 1H), 4.41 (d,
J¼12.4 Hz, 1H), 4.38 (d, J¼12.4 Hz, 1H), 4.36 (d, J¼15.8 Hz, 1H),
4.17e4.12 (br, 2H), 4.12e4.06 (br, 1H), 3.89e3.84 (br, 1H), 3.88 (s,
3H), 3.80 (s, 3H), 3.67e3.48 (br, 1H), 3.36e3.29 (m, 1H), 2.33 (s, 3H),
2.14 (d, J¼8.3 Hz, 1H), 1.78e1.68 (m, 1H), 1.68e1.52 (br, 2H),
1.52e1.43 (m, 1H), 1.02 (s, 9H); 13C NMR (150 MHz, CDCl3) d 148.06
(C), 147.50 (C), 143.22 (C), 138.51 (C), 137.56 (C), 135.41 (CH4),
133.41 (C2), 130.56 (CH), 129.71 (CH2), 129.28 (CH2), 129.11
(C), 128.49 (CH), 128.32 (CH2), 127.82 (C), 127.67 (CH4), 127.51
(CH2), 127.49 (CH3), 115.12 (CH), 112.64 (CH), 72.66 (CH), 69.36
(CH2), 63.73 (CH2), 63.48 (CH2), 56.00 (CH), 55.89 (CH3), 54.30
(CH3), 46.35 (CH), 29.68 (CH2), 27.28 (CH2), 26.78 (CH33), 26.64
(CH2), 21.45 (CH3), 19.20 (C).
4.4.5.4. Compound H. A mixture of G (25.1 mg, 30.6 mmol), 20%
Pd(OH)2eC (trace), and THF (0.5 mL) was stirred under H2 atmo-
sphere at room temperature for 15 h. The reaction mixture was
filtered and the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
eluted with AcOEt. To a solution of the resulting diol in CH2Cl2
(1 mL) was added TEMPO (2.2 mg, 6.8 mmol, 0.2 equiv) and
PhI(OAc)2 (94.6 mg, 0.605 mmol, 20 equiv) at room temperature.
After being stirred for 18 h, the reaction mixture was quenched
with saturated Na2S2O3 aqueous and extracted with CH2Cl2. The
extract was washed with saturated NaHCO3 and brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with n-
hexane/AcOEt (2:1) to give H (7.4 mg, 10.2 mmol, 32%, two steps) as
a colorless amorphous: [a]20 D 34.1 (c 0.370, CHCl3); IR (ATR) 2931,
1743, 1609; MS (FABþ) m/z 728 (MþHþ), 670, 650, 572; HRMS m/z
calcd for C41H50NO7SSi 728.3077; found 728.3085; 1H NMR
(600 MHz, CDCl3) d 7.61e7.56 (m, 4H), 7.42e7.32 (m, 8H), 7.10 (d,
J¼7.6 Hz, 2H), 6.59 (s, 1H), 6.45 (s, 1H), 4.68 (d, J¼15.8 Hz, 1H), 4.55
(dd, J¼10.3, 7.6 Hz, 1H), 4.54 (d, J¼15.8 Hz, 1H), 4.46 (t, J¼6.2 Hz,
1H), 3.89 (s, 3H), 3.70 (s, 3H), 3.64 (dt, J¼10.3, 6.2 Hz, 1H), 3.61e3.53
(m, 2H), 2.78e2.67 (m, 2H), 2.56 (dt, J¼17.2, 7.6 Hz, 1H), 2.36 (s, 3H),
2.32e2.23 (m, 1H), 2.22e2.16 (m, 1H), 2.11e2.03 (m, 1H), 1.45e1.36
(m, 1H), 1.35e1.25 (m, 1H), 1.00 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 170.34 (C), 148.24 (C), 147.35 (C), 143.11 (C), 137.51 (C), 135.49
(CH4), 133.86 (C), 133.80 (C), 130.31 (C), 129.56 (CH2), 129.30
(CH2), 127.60 (CH4), 126.75 (CH2), 126.54 (C), 113.47 (CH),
112.31 (CH), 80.33 (CH), 63.78 (CH2), 56.01 (CH3), 55.95 (CH3), 55.86
(CH), 49.85 (CH2), 47.47 (CH), 28.62 (CH2), 28.42 (CH2), 28.27 (CH2),
26.85 (CH33), 24.94 (CH2), 21.45 (CH3), 19.17 (C).
4.4.6. (3S,4R,5R)-4-(Benzyloxy)-3-[3-(benzyloxy)propyl]-5-[(tert-bu-
tyldiphenylsilyloxy)methyl]-7,8-dimethoxy-2-tosyl-2,3,4,5-
tetrahydro-1H-2-benzazepine (46). To a solution of 45 (1.35 g,
2.22 mmol) in CH2Cl2/MeOH (4:1 mixture, 25 mL) was stirred un-
der an ozone atmosphere (bubbling) at
70  C. After 2 h, the
mixture was diluted with CH2Cl2/MeOH (4:1 mixture, 80 mL). After
being stirred for 5 h, NaBH4 (267 mg, 6.66 mmol, after 5 h; 532 mg,
14.1 mmol, after 30 min) was added twice to the reaction mixture.
The mixture was stirred at room temperature for 13 h, then
quenched with H2O, and extracted with CHCl3. The extract was
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography eluted with n-
hexane/AcOEt (2:3) to give diol (659 mg, 54%) as a pale yellow oil.
To a solution of this diol (659 mg, 1.19 mmol) in CH2Cl2 (10 mL) was
added Et3N (0.33 mL, 2.38 mmol), DMAP (14.7 mg, 0.120 mmol),
and TBDPSCl (0.62 mL, 2.38 mmol) at room temperature. The
mixture was stirred for 14 h, then quenched with H2O, and
extracted with CHCl3. The extract was dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with n-hexane/AcOEt
(2:1) to give the silyl ether compound (837 mg, 1.06 mmol, 89%) as
a pale yellow oil. To a solution of this compound (800 mg,
1.02 mmol) in THF (12 mL) was added NaH (55% purity, 95.2 mg,
2.04 mmol) and BnBr (0.36 mL, 3.06 mmol) at 0  C. The mixture was
stirred at room temperature for 17 h, then quenched with H2O,
extracted with CHCl3, and washed with brine. The extract was dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel eluted with n-
hexane/AcOEt (2:1) to give 46 (803 mg, 0.908 mmol, 89%) as a pale
yellow oil: [a]20 D 22.6 (c 1.02, CHCl3); IR (neat) 2934, 1609,
1325 cm
1; EIMS m/z 883 (Mþ), 823, 725; HRMS m/z calcd for
C53H61NO7SSi 883.3938, found 883.3963; 1H NMR (400 MHz,
CDCl3) d 7.67 (d, J¼8.3 Hz, 2H), 7.54 (dd, J¼7.8, 1.2 Hz, 2H), 7.50 (dd,
J¼7.8, 1.2 Hz, 2H), 7.42e7.35 (m, 2H), 7.34e7.23 (m, 12H), 7.18 (dd,
J¼7.3, 3.6 Hz, 1H), 6.90 (d, J¼8.3 Hz, 1H), 6.70 (s, 1H), 6.33 (s, 1H),
4.67 (dd, J¼10.0, 5.1 Hz, 1H), 4.61 (d, J¼11.6 Hz, 1H), 4.46 (s, 2H),
4.38 (d, J¼14.6 Hz, 1H), 4.30 (d, J¼11.6 Hz, 1H), 4.25 (d, J¼14.6 Hz,
1H), 4.10 (dd, J¼10.3, 6.1 Hz, 1H), 3.95 (dd, J¼10.3, 7.1 Hz, 1H), 3.685
(s, 3H), 3.679 (s, 3H), 3.67e3.64 (m, 1H), 3.48 (dt, J¼9.3, 6.3 Hz, 1H),
3.39 (dt, J¼9.3, 6.1 Hz, 1H), 3.05 (dd, J¼12.8, 6.7 Hz, 1H), 2.25 (s, 3H),
1.77e1.67 (m, 1H), 1.45e1.32 (br, 1H), 1.31e1.17 (br, 1H), 1.00 (s, 9H);
13
C NMR (100 MHz, CDCl3) d 148.10 (C), 147.15 (C), 142.53 (C), 138.61
(C), 138.07 (C), 137.34 (C), 135.64 (CH2), 135.51 (CH2), 133.31 (C),
133.14 (C), 130.34 (C), 129.75 (CH2), 128.78 (CH2), 128.33
(CH4), 128.21 (CH2), 127.75 (CH2), 127.67 (CH2), 127.66
(CH2), 127.56 (CH2), 127.44 (CH2), 127.17 (C), 113.24 (CH),
112.29 (CH), 79.74 (CH), 72.76 (CH2), 70.80 (CH2), 69.60 (CH2), 63.33
(CH2), 58.84 (CH), 55.89 (CH3), 55.73 (CH3), 50.08 (CH), 47.25 (CH2),
28.66 (CH2), 27.25 (CH2), 26.91 (CH33), 21.38 (C), 19.18 (CH3).
4.4.7. (3S,4R,5R)-4-(Benzyloxy)-3-[3-(benzyloxy)propyl]-2,3,4,5-
tetrahydro-7,8-dimethoxy-2,5-methano-1H-2-benzazepine (47). To
a solution of 46 (803 mg, 0.908 mmol) in THF (10 mL) was added
TBAF (0.97 M in THF, 1.40 mL, 1.36 mmol) at room temperature. The
mixture was stirred for 2 h, then quenched with H2O, extracted
with CHCl3, and washed with brine. The extract was dried over
MgSO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel eluted with n-
hexane/AcOEt (1:2) to give alcohol (568 mg, 0.880 mmol, 97%) as
a pale yellow oil. To a 1.6 M solution of naphthalene (2.00 g,
16.4 mmol) in DME (10 mL) was added sodium (0.40 g, 17.4 mmol)
at room temperature. To a solution of the alcohol (1.17 g, 1.81 mmol)
in DME (20 mL) was added dropwise a 1.6 M solution of naphtha-
lene in DME until the resulting solution remained blue at
70  C
under an argon atmosphere. The mixture was quenched with H2O,
extracted with CHCl3, and washed with brine. The extract was dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel eluted with
ammoniaesaturated CHCl3/MeOH (9:1) to give amine (0.93 g) as
a pale yellow oil. To a solution of this amine in CH3CN (5 mL) and
Et2O (10 mL) were added Ph3P (1.00 g, 3.81 mmol), imidazole
(420 mg, 6.17 mmol), and I2 (1.02 g, 4.02 mmol) at room temper-
ature. After being stirred for 18 h, the mixture was quenched with
saturated aqueous NaHCO3 and saturated aqueous Na2S2O3 and
extracted with CHCl3. The extract was dried over MgSO4 and con-
centrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with AcOEt and on
alumina eluted with n-hexane/AcOEt (2:1) to give 47 (704 mg,
1.48 mmol, 82%) as a pale yellow oil: [a]20
D
95.0 (c 1.063, CHCl3); IR
(neat) 2936, 2858, 1609, 1516; EIMS m/z 473 (Mþ), 383, 354, 290,
260 cm
1; HRMS m/z calcd for C30H35NO4S 473.2566; found
473.2542; 1H NMR (400 MHz, CDCl3) d 7.35e7.17 (m, 10H), 6.53 (s,
1H), 6.51 (s, 1H), 4.65 (d, J¼11.5 Hz, 1H), 4.49 (s, 2H), 4.45 (d,
J¼11.5 Hz, 1H), 4.35 (d, J¼16.6 Hz, 1H), 3.94 (t, J¼5.1 Hz, 1H), 3.83 (s,
3H), 3.80 (s, 3H), 3.75 (d, J¼16.6 Hz, 1H), 3.55e3.44 (m, 2H), 3.13
(dd, J¼11.8, 2.4 Hz, 1H), 3.08 (q, J¼2.4 Hz, 1H), 3.02 (dd, J¼11.8,
2.4 Hz, 1H), 2.75e2.65 (m, 1H), 1.88e1.75 (m, 1H), 1.74e1.50 (m,
 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
3H); 13C NMR (100 MHz, CDCl3) d 148.16 (C), 146.76 (C), 138.59 (C),
137.93 (C), 129.99 (C), 128.22 (CH4), 127.67 (CH2), 127.59
(CH2), 127.50 (CH), 127.33 (CH), 124.94 (C), 112.17 (CH), 109.30
(CH), 93.64 (CH), 72.74 (CH2), 72.34 (CH2), 70.21 (CH2), 69.48 (CH),
61.04 (CH2), 55.97 (CH3), 55.74 (CH3), 52.81 (CH2), 41.64 (CH), 32.02
(CH2), 27.60 (CH2).
4.4.8. (2R,3S,4R,5R)-3-[3-(tert-Butyldiphenylsilyloxy)propyl]-7,8-
dimethoxy-1,3,4,5-tetrahydro-2,5-methano-1H-2-benzazepin-4-yl
acetate (48). To a solution of 47 (335 mg, 0.708 mmol) in MeOH
(4 mL) were added 20% Pd(OH)2eC (43.5 mg, 62 mmol) and con-
centrated HCl (several drops) at 0  C. The mixture was stirred under
H2 atmosphere at room temperature for 2 h, then quenched with
K2CO3 and MgSO4. The mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluted with ammoniaesatu-
rated CHCl3/MeOH (9:1) to give diol (199 mg, 0.680 mmol, 96%) as
a pale yellow oil. To a solution of this diol (193 mg, 0.658 mmol) in
CH2Cl2 (3 mL) was added Et3N (0.20 mL, 1.44 mmol), DMAP
(10.4 mg, 8.5 mmol), and TBDPSCl (0.35 mL, 1.35 mmol) at room
temperature. The mixture was stirred for 1 h, then quenched with
H2O, and extracted with CHCl3. The extract was dried over MgSO4
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel eluted with ammo-
niaesaturated CHCl3/MeOH (9:1) to give silyl ether (319 mg,
0.619 mmol, 91%) as a colorless needle. To a solution of the silyl
ether (231 mg, 0.435 mmol) in pyridine (2 mL) were added Ac2O
(0.10 mL, 1.06 mmol) and DMAP (10.4 mg, 8.5 mmol) at room
temperature. The mixture was stirred for 1 h, then quenched with
saturated aqueous NaHCO3 and extracted with CHCl3. The extract
was dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
eluted with ammoniaesaturated CHCl3 to give 48 (217 mg,
0.378 mmol, 87%) as a pale yellow oil: [a]20 D
92.3 (c 1.03, CHCl3); IR
(neat) 2936, 1738, 1516 cm
1; EIMS m/z 573 (Mþ), 516, 457; HRMS
m/z calcd for C34H43NO5Si 573.2911, found 573.2886; 1H NMR
(400 MHz, CDCl3) d 7.70e7.63 (m, 4H), 7.45e7.32 (m, 6H), 6.50 (s,
1H), 6.37 (s, 1H), 4.84 (t, J¼5.2 Hz, 1H), 4.36 (d, J¼6.8 Hz, 1H), 3.84 (s,
3H), 3.81 (s, 3H), 3.76e3.64 (m, 3H), 3.31 (dd, J¼5.2, 2.4 Hz, 1H), 3.18
(dd, J¼12.0, 2.4 Hz, 1H), 3.04 (dd, J¼12.0, 2.0 Hz, 1H), 2.89e2.80 (m,
1H), 1.83 (s, 3H), 1.79e1.69 (m, 2H), 1.68e1.58 (m, 2H), 1.03 (s, 9H);
13
C NMR (100 MHz, CDCl3) d 171.25 (C), 148.25 (C), 147.00 (C), 135.58
(CH4), 133.94 (C2), 129.65 (C), 129.52 (CH2), 127.60 (CH4),
124.74 (C), 111.28 (CH), 109.20 (CH), 88.25 (CH), 68.68 (CH), 63.68
(CH2), 60.87 (CH2), 56.04 (CH3), 55.84 (CH3), 52.79 (CH2), 41.86
(CH), 31.47 (CH2), 30.02 (CH2), 26.85 (CH33), 21.04 (CH3), 19.22 (C).
4.4.9. (2R,3S,4R,5R)-7,8-Dimethoxy-3-(3-oxopropyl)-1,3,4,5-
tetrahydro-2,5-methano-1H-2-benzazepin-4-yl acetate (49). To
a solution of 48 (214 mg, 0.373 mmol) in THF (2 mL) was added
TBAF (1.0 M in THF, 0.56 mL, 0.56 mmol) at room temperature. The
mixture was stirred for 6 h, then quenched with H2O, and extracted
with CHCl3. The extract was washed with saturated aqueous
NaHCO3, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with ammoniaesaturated CHCl3/MeOH (9:1) to
give alcohol (124 mg, 0.370 mmol, 99%) as a pale yellow oil. To
a solution of the alcohol (124 mg, 0.370 mmol) in CH2Cl2 (2 mL)
were added DesseMartin periodinane (0.24 g, 0.56 mmol) and
pyridine (0.18 mL, 2.2 mmol) at 0  C. The mixture was stirred at 0  C
for 1 h and at room temperature for 2 h, then quenched with sat-
urated aqueous NaHCO3 and extracted with CHCl3. The extract was
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel eluted
with ammoniaesaturated CHCl3/MeOH (9:1) to give the aldehyde
49 (103 mg, 0.306 mmol, 83%) as a pale yellow oil: 1H NMR
4137
(400 MHz, CDCl3) d 9.58 (br s, 1H), 6.52 (s, 1H), 6.38 (s, 1H), 4.87 (t,
J¼4.9 Hz, 1H), 4.35 (d, J¼16.1 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.70
(d, J¼16.1 Hz, 1H), 3.35e3.30 (m, 1H), 3.18 (d, J¼11.8 Hz, 1H), 3.05 (d,
J¼11.8 Hz, 1H), 2.86e2.77 (m, 1H), 2.58e2.50 (m, 1H), 1.87 (s, 3H).
4.4.10. (3S,4R,5R)-4-Hydroxy-3-(3-hydroxy)-butyl-2,3,4,5-
tetrahydro-7,8-dimethoxy-2,5-methano-1H-2-benzazepine (51). To
a solution of 49 (91.7 mg, 0.275 mmol) in THF (2.5 mL) was added
dropwise MeMgBr (0.96 M in THF, 0.46 mL, 0.442 mmol) at room
temperature. The mixture was stirred for 3 h, then quenched with
saturated aqueous NaHCO3, and extracted with CHCl3. The extract
was dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
eluted with ammoniaesaturated CHCl3/MeOH (9:1) to give 50
(40.3 mg, 0.110 mmol, 40%) and 51 (17.1 mg, 44.0 mmol, 16%) as pale
yellow oils. Compounds 50 and 51 are, respectively, epimeric
mixtures. Subsequently, 50 was dissolved in saturated K2CO3/
MeOH solution (0.8 mL) and the resulting mixture was stirred at
room temperature for 8 h. The mixture was quenched with satu-
rated aqueous NaHCO3 and extracted with CHCl3. The extract was
dried over MgSO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel eluted
with ammoniaesaturated CHCl3/MeOH (9:1) to give 51 (17.4 mg,
53.9 mmol, 49%) as a pale yellow oil: IR (ATR) 3280, 2924,
1512 cm
1; MS (FABþ) m/z 308 (MþHþ), 284, 276; HRMS m/z calcd
for C17H26NO4 308.1862; found 308.1841; 1H NMR (400 MHz, CDCl3,
ratio of epimers. ca. 1:1) d 6.59 and 6.58 (s, 1H), 6.55 and 6.54 (s, 1H),
4.36 (d, J¼16.8 Hz, 1H), 4.11 (dt, J¼17.3, 5.0 Hz, 1H), 3.88 and 3.87 (s,
3H), 3.85 (s, 3H), 3.79 and 3.77 (d, J¼17.0 Hz, 1H), 3.18 (dt, J¼12.0,
2.3 Hz, 1H), 3.02 d, J¼12.0 Hz, 1H), 2.92 (ddd, J¼12.0, 5.3, 2.3 Hz, 1H),
2.49e2.38 (m, 1H), 2.08e1.03 (m, 5H), 1.19 (t, J¼6.0 Hz, 3H).
4.4.11. (3S,5R)-2,3,4,5-Tetrahydro-7,8-dimethoxy-3-(3-oxo-butyl)-
2,5-methano-1H-2-benzazepin-4-one (52). To a solution of 51
(51.3 mg, 0.167 mmol) in CH2Cl2 (1 mL) were added MS4A (198 mg),
NMO (12.0 mg, 0.102 mmol), and TPAP (5.7 mg, 16.2 mmol) at room
temperature. After being stirred for 1 h, NMO (24.0 mg, 0.204 mmol)
was added to the reaction mixture. After 1 h, the mixture was filtered
though a florisil short column and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with AcOEt to give 52 (11.2 mg) as a white powder,
and eluted with ammoniaesaturated CHCl3 to give the mono ketone
(20.7 mg) as a pale yellow oil. Mono ketone was subjected to TPAP
oxidation again giving 52 (15.5 mg) as a white powder. Totally, 52
(26.7 mg, 88.1 mmol) was obtained from 51 in 53% yield: [a]20 D
229
(c 1.12, CHCl3); IR (ATR) 2923, 1712, 1603 cm
1; EIMS m/z 303 (Mþ),
275, 260, 232; HRMS m/z calcd for C17H21NO4 303.1471; found
303.1493; 1H NMR (400 MHz, CDCl3) d 6.61 (s, 1H), 6.51 (s, 1H), 4.50
(d, J¼17.2 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.72 (d, J¼17.2 Hz, 1H),
3.44 (dd, J¼12.6 Hz, 2.3 Hz, 1H), 3.20 (d, J¼2.8 Hz, 1H), 3.05e2.98 (m,
2H), 2.73 (dt, J¼17.5, 7.0 Hz, 1H), 2.64 (dt, J¼17.5, 7.1 Hz, 1H), 2.18 (s,
3H), 2.05e1.93 (m, 1H), 1.85e1.73 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 212.51 (C), 208.10 (C), 149.22 (C), 128.41 (C), 125.89 (C), 123.50 (C),
109.93 (CH), 109.13 (CH), 68.95 (CH), 59.05 (CH2), 55.97 (CH3), 55.95
(CH3), 51.60 (CH2), 49.53 (CH), 40.50 (CH2), 30.05 (CH3), 24.81 (CH2).
4.4.12. Aldol (53) and enone (54). To a solution of 52 (20.5 mg,
67.6 mmol) in EtOH (0.5 mL) was added KOH (3.5 mg, 62.4 mmol) at
room temperature. The mixture was stirred for 6 h, then quenched
with saturated aqueous NH4Cl, and saturated aqueous NaHCO3. The
mixture was extracted with CHCl3 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with CHCl3/MeOH (9:1) to give 53 (13.1 mg,
43.3 mmol, 64%) as a white powder, and 54 (2.3 mg, 8.1 mmol, 12%) as
a pale yellow oil. Subsequently, to a solution of 53 (2.7 mg,
8.9 mmol) in EtOH (0.2 mL) was added KOH (2.24 mg, 39.9 mmol) at
4138 M. Mizukami et al. / Tetrahedron 69 (2013) 4120e4138
room temperature. The mixture was stirred for 1 h, and was
warmed at 60  C. After being stirred for 1 h, then quenched with
saturated aqueous NH4Cl and saturated aqueous NaHCO3. The
mixture was extracted with CHCl3 and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluted with CHCl3/MeOH (9:1) to give 54 (1.3 mg,
4.5 mmol, 52%) as a pale yellow oil.
Aldol (53): [a]20
D
266 (c 0.85, CHCl3); IR (CHCl3) 3580, 1720,
1420 cm
1; EIMS m/z 303 (Mþ), 285, 274, 260; HRMS m/z calcd for
C17H21NO4 303.1471; found 303.1488; 1H NMR (400 MHz, CDCl3)
d 6.58 (s, 1H), 6.57 (s, 1H), 4.45 (d, J¼17.1 Hz, 1H), 3.90 (d, J¼17.1 Hz,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.37 (dd, J¼12.3, 2.7 Hz, 1H), 3.12 (dd,
J¼12.3, 1.7 Hz), 2.90e2.83 (m, 1H), 2.87 (d, J¼15.8 Hz, 1H), 2.65 (d,
J¼2.2 Hz, 1H), 2.60 (d, J¼15.8 Hz, 1H), 2.49e2.40 (m, 1H), 2.33e2.20
(m, 2H), 2.86e1.72 (m, 1H), 1.58 (br s, 1H); 13C NMR (100 MHz,
CDCl3) d 209.87 (C), 149.07 (C), 127.57 (C), 127.91 (C), 124.75 (C),
112.47 (CH), 109.45 (CH), 86.72 (C), 72.76 (CH), 60.71 (CH2), 56.04
(CH3), 55.97 (CH3), 53.53 (CH2), 49.80 (CH), 47.35 (CH2), 35.72 (CH2),
26.26 (CH2).
Enone (54). A pale yellow oil: [a]20D
181 (c 0.23, CHCl3); IR (neat)
2922, 1669, 1516 cm
1; EIMS m/z 285 (Mþ), 257, 229; HRMS m/z
calcd for C17H19NO4 285.1365; found 285.1362; 1H NMR (400 MHz,
CDCl3) d 6.58 (s, 1H), 6.54 (s, 1H), 5.93 (s, 1H), 4.44 (d, J¼16.7 Hz, 1H),
3.91 (d, J¼16.7 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.62e3.54 (m, 1H),
3.47 (d, J¼2.0 Hz, 1H), 3.27e3.15 (m, 2H), 2.60e2.50 (m, 1H),
2.42e2.22 (m, 2H), 1.95e1.80 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 198.85 (C), 176.36 (C), 148.99 (C), 147.89 (C), 129.26 (C), 123.14 (C),
117.36 (CH), 110.37 (CH), 109.71 (CH), 64.70 (CH), 60.51 (CH2), 56.05
(CH3), 56.00 (CH3), 55.11 (CH2), 45.91 (CH), 37.22 (CH2), 30.68 (CH2).
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search (C) (15590017 to S.N.). We wish dedicate this study to Dr.
Masanori SAKAMOTO, Professor Emeritus of Meiji Pharmaceutical
University, on the occasion of his 77th birthday (KIJU).
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http://dx.doi.org/10.1186/1860-5397-3-8